Inhibitors of bruton&#39;s tyrosine kinase

ABSTRACT

This application discloses compounds according to generic Formula (I): wherein all variables are defined as described herein, which inhibit BTK. The compounds disclosed herein are useful to modulate the activity of BTK and treat diseases associated with excessive BTK activity. The compounds are further useful to treat inflammatory and auto immune diseases associated with aberrant B-cell proliferation such as rheumatoid arthritis. Also disclosed are compositions containing compounds of Formula I and at least one carrier, diluent or excipient.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Stage Application of PCT/EP2014/054018filed Mar. 3, 2014, which claims priority from U.S. Provisional PatentApplication No. 61/772,954, filed on Mar. 5, 2013. The priority of bothsaid PCT and U.S. Provisional Patent Application are claimed. Each ofthe prior mentioned applications is hereby incorporated by referenceherein in its entirety.

FIELD OF THE INVENTION

The present invention relates to the use of novel compounds whichinhibit BTK and are useful for the treatment of auto-immune andinflammatory diseases caused by aberrant B-cell activation.

BACKGROUND OF THE INVENTION

Protein kinases constitute one of the largest families of human enzymesand regulate many different signaling processes by adding phosphategroups to proteins (T. Hunter, Cell 1987 50:823-829). Specifically,tyrosine kinases phosphorylate proteins on the phenolic moiety oftyrosine residues. The tyrosine kinase family includes members thatcontrol cell growth, migration, and differentiation. Abnormal kinaseactivity has been implicated in a variety of human diseases includingcancers, autoimmune and inflammatory diseases. Since protein kinases areamong the key regulators of cell signaling they provide a target tomodulate cellular function with small molecular kinase inhibitors andthus make good drug design targets. In addition to treatment ofkinase-mediated disease processes, selective and efficacious inhibitorsof kinase activity are also useful for investigation of cell signalingprocesses and identification of other cellular targets of therapeuticinterest.

There is good evidence that B-cells play a key role in the pathogenesisof autoimmune and/or inflammatory disease. Protein-based therapeuticsthat deplete B cells such as Rituxan are effective againstautoantibody-driven inflammatory diseases such as rheumatoid arthritis(Rastetter et al. Annu Rev Med 2004 55:477). Therefore inhibitors of theprotein kinases that play a role in B-cell activation should be usefultherapeutics for B-cell mediated disease pathology such as autoantibodyproduction.

Signaling through the B-cell receptor (BCR) controls a range of B-cellresponses including proliferation and differentiation into matureantibody producing cells. The BCR is a key regulatory point for B-cellactivity and aberrant signaling can cause deregulated B-cellproliferation and formation of pathogenic autoantibodies that lead tomultiple autoimmune and/or inflammatory diseases. Bruton's TyrosineKinase (BTK) is a non-BCR associated kinase that is membrane proximaland immediately downstream from BCR. Lack of BTK has been shown to blockBCR signaling and therefore inhibition of BTK could be a usefultherapeutic approach to block B-cell mediated disease processes.

BTK is a member of the Tec family of tyrosine kinases, and has beenshown to be a critical regulator of early B-cell development and matureB-cell activation and survival (Khan et al. Immunity 1995 3:283;Ellmeier et al. J. Exp. Med. 2000 192:1611). Mutation of BTK in humansleads to the condition X-linked agammaglobulinemia (XLA) (reviewed inRosen et al. New Eng. J. Med. 1995 333:431 and Lindvall et al. Immunol.Rev. 2005 203:200). These patients are immunocompromised and showimpaired maturation of B-cells, decreased immunoglobulin and peripheralB-cell levels, diminished T-cell independent immune responses as well asattenuated calcium mobilization following BCR stimulation.

Evidence for a role for BTK in autoimmune and inflammatory diseases hasalso been provided by BTK-deficient mouse models. In preclinical murinemodels of systemic lupus erythematosus (SLE), BTK-deficient mice showmarked amelioration of disease progression. In addition, BTK-deficientmice are resistant to collagen-induced arthritis (Jansson and HolmdahlClin. Exp. Immunol. 1993 94:459). A selective BTK inhibitor has beendemonstrated dose-dependent efficacy in a mouse arthritis model (Z. Panet al., Chem. Med Chem. 2007 2:58-61).

BTK is also expressed by cells other than B-cells that may be involvedin disease processes. For example, BTK is expressed by mast cells andBTK-deficient bone marrow derived mast cells demonstrate impairedantigen induced degranulation (Iwaki et al. J. Biol. Chem. 2005280:40261). This shows BTK could be useful to treat pathological mastcells responses such as allergy and asthma. Also monocytes from XLApatients, in which BTK activity is absent, show decreased TNF alphaproduction following stimulation (Horwood et al. J Exp Med 197:1603,2003). Therefore TNF alpha mediated inflammation could be modulated bysmall molecular BTK inhibitors. Also, BTK has been reported to play arole in apoptosis (Islam and Smith Immunol. Rev. 2000 178:49) and thusBTK inhibitors would be useful for the treatment of certain B-celllymphomas and leukemias (Feldhahn et al. J. Exp. Med. 2005 201:1837).

SUMMARY OF THE INVENTION

The present application provides the BTK inhibitor compounds of FormulaI, methods of use thereof, as described herein below:

The application provides a compound of Formula I,

wherein:

-   n is 1 or 2;-   R¹ is —C(═O)R¹, —S(═O)₂R¹, or —OC(R¹)₂CH₂OH;    -   R^(1′) is methyl or morpholine;-   R² is H or F;-   R³ is chloro or C(CH₂)₂R^(3′);    -   R^(3′) is methyl, cyano, or hydroxymethyl;-   X is CH, CH₂, or N;-   X² is CH or N;-   X³ is CH or N; and-   Y is CH or O;-   with the proviso that when n is 2, both X are CH₂;-   or a pharmaceutically acceptable salt thereof.

The application provides a method for treating an inflammatory and/orautoimmune condition comprising administering to a patient in needthereof a therapeutically effective amount of the compound of Formula I.

The application provides a pharmaceutical composition comprising thecompound of Formula I, admixed with at least one pharmaceuticallyacceptable carrier, excipient or diluent.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The phrase “a” or “an” entity as used herein refers to one or more ofthat entity; for example, a compound refers to one or more compounds orat least one compound. As such, the terms “a” (or “an”), “one or more”,and “at least one” can be used interchangeably herein.

The phrase “as defined herein above” refers to the broadest definitionfor each group as provided in the Summary of the Invention or thebroadest claim. In all other embodiments provided below, substituentswhich can be present in each embodiment and which are not explicitlydefined retain the broadest definition provided in the Summary of theInvention.

As used in this specification, whether in a transitional phrase or inthe body of the claim, the terms “comprise(s)” and “comprising” are tobe interpreted as having an open-ended meaning. That is, the terms areto be interpreted synonymously with the phrases “having at least” or“including at least”. When used in the context of a process, the term“comprising” means that the process includes at least the recited steps,but may include additional steps. When used in the context of a compoundor composition, the term “comprising” means that the compound orcomposition includes at least the recited features or components, butmay also include additional features or components.

As used herein, unless specifically indicated otherwise, the word “or”is used in the “inclusive” sense of “and/or” and not the “exclusive”sense of “either/or”.

The term “independently” is used herein to indicate that a variable isapplied in any one instance without regard to the presence or absence ofa variable having that same or a different definition within the samecompound. Thus, in a compound in which R″ appears twice and is definedas “independently carbon or nitrogen”, both R″s can be carbon, both R″scan be nitrogen, or one R″ can be carbon and the other nitrogen.

When any variable occurs more than one time in any moiety or formuladepicting and describing compounds employed or claimed in the presentinvention, its definition on each occurrence is independent of itsdefinition at every other occurrence. Also, combinations of substituentsand/or variables are permissible only if such compounds result in stablecompounds.

The symbols “*” at the end of a bond or “- - - ” drawn through a bondeach refer to the point of attachment of a functional group or otherchemical moiety to the rest of the molecule of which it is a part. Thus,for example:

A bond drawn into ring system (as opposed to connected at a distinctvertex) indicates that the bond may be attached to any of the suitablering atoms.

The term “optional” or “optionally” as used herein means that asubsequently described event or circumstance may, but need not, occur,and that the description includes instances where the event orcircumstance occurs and instances in which it does not. For example,“optionally substituted” means that the optionally substituted moietymay incorporate a hydrogen atom or a substituent.

The phrase “optional bond” means that the bond may or may not bepresent, and that the description includes single, double, or triplebonds. If a substituent is designated to be a “bond” or “absent”, theatoms linked to the substituents are then directly connected.

The term “about” is used herein to mean approximately, in the region of,roughly, or around. When the term “about” is used in conjunction with anumerical range, it modifies that range by extending the boundariesabove and below the numerical values set forth. In general, the term“about” is used herein to modify a numerical value above and below thestated value by a variance of 20%.

Certain compounds of Formulae I may exhibit tautomerism. Tautomericcompounds can exist as two or more interconvertable species. Prototropictautomers result from the migration of a covalently bonded hydrogen atombetween two atoms. Tautomers generally exist in equilibrium and attemptsto isolate an individual tautomers usually produce a mixture whosechemical and physical properties are consistent with a mixture ofcompounds. The position of the equilibrium is dependent on chemicalfeatures within the molecule. For example, in many aliphatic aldehydesand ketones, such as acetaldehyde, the keto form predominates while; inphenols, the enol form predominates. Common prototropic tautomersinclude keto/enol (—C(═O)—CH—⇄—C(—OH)═CH—), amide/imidic acid(—C(═O)—NH—⇄—C(—OH)═N—) and amidine (—C(═NR)—NH—⇄—C(—NHR)═N—) tautomers.The latter two are particularly common in heteroaryl and heterocyclicrings and the present invention encompasses all tautomeric forms of thecompounds.

Technical and scientific terms used herein have the meaning commonlyunderstood by one of skill in the art to which the present inventionpertains, unless otherwise defined. Reference is made herein to variousmethodologies and materials known to those of skill in the art. Standardreference works setting forth the general principles of pharmacologyinclude Goodman and Gilman's The Pharmacological Basis of Therapeutics,10^(th) Ed., McGraw Hill Companies Inc., New York (2001). Any suitablematerials and/or methods known to those of skill can be utilized incarrying out the present invention. However, preferred materials andmethods are described. Materials, reagents and the like to whichreference are made in the following description and examples areobtainable from commercial sources, unless otherwise noted.

The definitions described herein may be appended to formchemically-relevant combinations, such as “heteroalkylaryl”,“haloalkylheteroaryl”, “arylalkylheterocyclyl”, “alkylcarbonyl”,“alkoxyalkyl”, and the like. When the term “alkyl” is used as a suffixfollowing another term, as in “phenylalkyl”, or “hydroxyalkyl”, this isintended to refer to an alkyl group, as defined above, being substitutedwith one to two substituents selected from the other specifically-namedgroup. Thus, for example, “phenylalkyl” refers to an alkyl group havingone to two phenyl substituents, and thus includes benzyl, phenylethyl,and biphenyl. An “alkylaminoalkyl” is an alkyl group having one to twoalkylamino substituents. “Hydroxyalkyl” includes 2-hydroxyethyl,2-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl,2,3-dihydroxybutyl, 2-(hydroxymethyl), 3-hydroxypropyl, and so forth.Accordingly, as used herein, the term “hydroxyalkyl” is used to define asubset of heteroalkyl groups defined below. The term -(ar)alkyl refersto either an unsubstituted alkyl or an aralkyl group. The term(hetero)aryl or (het)aryl refers to either an aryl or a heteroarylgroup.

The term “spirocycloalkyl”, as used herein, means a spirocycliccycloalkyl group, such as, for example, spiro[3.3]heptane. The termspiroheterocycloalkyl, as used herein, means a spirocyclicheterocycloalkyl, such as, for example, 2,6-diaza spiro[3.3]heptane.

The term “acyl” as used herein denotes a group of formula —C(═O)Rwherein R is hydrogen or lower alkyl as defined herein. The term or“alkylcarbonyl” as used herein denotes a group of formula C(═O)R whereinR is alkyl as defined herein. The term C₁₋₆ acyl refers to a group—C(═O)R contain 6 carbon atoms. The term “arylcarbonyl” as used hereinmeans a group of formula C(═O)R wherein R is an aryl group; the term“benzoyl” as used herein an “arylcarbonyl” group wherein R is phenyl.

The term “ester” as used herein denotes a group of formula —C(═O)ORwherein R is lower alkyl as defined herein.

The term “alkyl” as used herein denotes an unbranched or branched chain,saturated, monovalent hydrocarbon residue containing 1 to 10 carbonatoms. The term “lower alkyl” denotes a straight or branched chainhydrocarbon residue containing 1 to 6 carbon atoms. “C₁₋₁₀ alkyl” asused herein refers to an alkyl composed of 1 to 10 carbons. Examples ofalkyl groups include, but are not limited to, lower alkyl groups includemethyl, ethyl, propyl, i-propyl, n-butyl, i-butyl, t-butyl or pentyl,isopentyl, neopentyl, hexyl, heptyl, and octyl.

When the term “alkyl” is used as a suffix following another term, as in“phenylalkyl”, or “hydroxyalkyl”, this is intended to refer to an alkylgroup, as defined above, being substituted with one to two substituentsselected from the other specifically-named group. Thus, for example,“phenylalkyl” denotes the radical R′R″—, wherein R′ is a phenyl radical,and R″ is an alkylene radical as defined herein with the understandingthat the attachment point of the phenylalkyl moiety will be on thealkylene radical. Examples of arylalkyl radicals include, but are notlimited to, benzyl, phenylethyl, 3-phenylpropyl. The terms “arylalkyl”or “aralkyl” are interpreted similarly except R′ is an aryl radical. Theterms “(het)arylalkyl” or “(het)aralkyl” are interpreted similarlyexcept R′ is optionally an aryl or a heteroaryl radical.

The terms “haloalkyl” or “halo-lower alkyl” or “lower haloalkyl” refersto a straight or branched chain hydrocarbon residue containing 1 to 6carbon atoms wherein one or more carbon atoms are substituted with oneor more halogen atoms.

The term “alkylene” or “alkylenyl” as used herein denotes a divalentsaturated linear hydrocarbon radical of 1 to 10 carbon atoms (e.g.,(CH₂)_(n)) or a branched saturated divalent hydrocarbon radical of 2 to10 carbon atoms (e.g., —CHMe- or —CH₂CH(i-Pr)CH₂—), unless otherwiseindicated. Except in the case of methylene, the open valences of analkylene group are not attached to the same atom. Examples of alkyleneradicals include, but are not limited to, methylene, ethylene,propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, butylene,2-ethylbutylene.

The term “alkoxy” as used herein means an —O-alkyl group, wherein alkylis as defined above such as methoxy, ethoxy, n-propyloxy, i-propyloxy,n-butyloxy, i-butyloxy, t-butyloxy, pentyloxy, hexyloxy, including theirisomers. “Lower alkoxy” as used herein denotes an alkoxy group with a“lower alkyl” group as previously defined. “C₁₋₁₀ alkoxy” as used hereinrefers to an —O-alkyl wherein alkyl is C₁₋₁₀.

The term “PCy₃” refers to a phosphine trisubstituted with three cyclicmoieties.

The terms “haloalkoxy” or “halo-lower alkoxy” or “lower haloalkoxy”refers to a lower alkoxy group, wherein one or more carbon atoms aresubstituted with one or more halogen atoms.

The term “hydroxyalkyl” as used herein denotes an alkyl radical asherein defined wherein one to three hydrogen atoms on different carbonatoms is/are replaced by hydroxyl groups.

The terms “alkylsulfonyl” and “arylsulfonyl” as used herein refers to agroup of formula —S(═O)₂R wherein R is alkyl or aryl respectively andalkyl and aryl are as defined herein. The term “heteroalkylsulfonyl” asused herein refers herein denotes a group of formula —S(═O)₂R wherein Ris “heteroalkyl” as defined herein.

The terms “alkylsulfonylamino” and “arylsulfonylamino” as used hereinrefers to a group of formula —NR′S(═O)₂R wherein R is alkyl or arylrespectively, R′ is hydrogen or C₁₋₃ alkyl, and alkyl and aryl are asdefined herein.

The term “cycloalkyl” as used herein refers to a saturated carbocyclicring containing 3 to 8 carbon atoms, i.e. cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. “C₃₋₇ cycloalkyl” asused herein refers to a cycloalkyl composed of 3 to 7 carbons in thecarbocyclic ring.

The term “carboxy-alkyl” as used herein refers to an alkyl moietywherein one, hydrogen atom has been replaced with a carboxyl with theunderstanding that the point of attachment of the heteroalkyl radical isthrough a carbon atom. The term “carboxy” or “carboxyl” refers to a—CO₂H moiety.

The term “heteroaryl” or “heteroaromatic” as used herein means amonocyclic or bicyclic radical of 5 to 12 ring atoms having at least onearomatic or partially unsaturated ring containing four to eight atomsper ring, incorporating one or more N, O, or S heteroatoms, theremaining ring atoms being carbon, with the understanding that theattachment point of the heteroaryl radical will be on an aromatic orpartially unsaturated ring. As well known to those skilled in the art,heteroaryl rings have less aromatic character than their all-carboncounter parts. Thus, for the purposes of the invention, a heteroarylgroup need only have some degree of aromatic character. Examples ofheteroaryl moieties include monocyclic aromatic heterocycles having 5 to6 ring atoms and 1 to 3 heteroatoms include, but is not limited to,pyridinyl, pyrimidinyl, pyrazinyl, oxazinyl, pyrrolyl, pyrazolyl,imidazolyl, oxazolyl, 4,5-Dihydro-oxazolyl,5,6-Dihydro-4H-[1,3]oxazolyl, isoxazole, thiazole, isothiazole,triazoline, thiadiazole and oxadiaxoline which can optionally besubstituted with one or more, preferably one or two substituentsselected from hydroxy, cyano, alkyl, alkoxy, thio, lower haloalkoxy,alkylthio, halo, lower haloalkyl, alkylsulfinyl, alkylsulfonyl, halogen,amino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, anddialkylaminoalkyl, nitro, alkoxycarbonyl and carbamoyl, alkylcarbamoyl,dialkylcarbamoyl, arylcarbamoyl, alkylcarbonylamino andarylcarbonylamino. Examples of bicyclic moieties include, but are notlimited to, quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl,benzoxazole, benzisoxazole, benzothiazole, naphthyridinyl,5,6,7,8-Tetrahydro-[1,6]naphthyridinyl, and benzisothiazole. Bicyclicmoieties can be optionally substituted on either ring, however the pointof attachment is on a ring containing a heteroatom.

The term “heterocyclyl”, “heterocycloalkyl” or “heterocycle” as usedherein denotes a monovalent saturated cyclic radical, consisting of oneor more rings, preferably one to two rings, including spirocyclic ringsystems, of three to eight atoms per ring, incorporating one or morering heteroatoms (chosen from N, O or S(O)₀₋₂), and which can optionallybe independently substituted with one or more, preferably one or twosubstituents selected from hydroxy, oxo, cyano, lower alkyl, loweralkoxy, lower haloalkoxy, alkylthio, halo, lower haloalkyl,hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl,arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino,arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl,alkylcarbonylamino, arylcarbonylamino, and ionic forms thereof, unlessotherwise indicated. Examples of heterocyclic radicals include, but arenot limited to, morpholinyl, piperazinyl, piperidinyl, azetidinyl,pyrrolidinyl, hexahydroazepinyl, oxetanyl, tetrahydrofuranyl,tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl,tetrahydropyranyl, thiomorpholinyl, quinuclidinyl and imidazolinyl, andionic forms thereof. Examples may also be bicyclic, such as, forexample, 3,8-diaza-bicyclo[3.2.1]octane, 2,5-diaza-bicyclo[2.2.2]octane,or octahydro-pyrazino[2,1-c][1,4]oxazine.

Inhibitors of BTK

The application provides a compound of Formula I,

wherein:

-   n is 1 or 2;-   R¹ is —C(═O)R^(1′), —S(═O)₂R^(1′), or —OC(R^(1′))₂CH₂OH;    -   R¹ is methyl or morpholine;-   R² is H or F;-   R³ is chloro or C(CH₂)₂R^(3′);    -   R^(3′) is methyl, cyano, or hydroxymethyl;-   X is CH, CH₂, or N;-   X² is CH or N;-   X³ is CH or N; and-   Y is CH or O;-   with the proviso that when n is 2, both X are CH₂;-   or a pharmaceutically acceptable salt thereof.

The application provides a compound of Formula I, wherein R² is H.

The application provides the above compound of Formula I, wherein R³ istert-butyl.

The application provides the above compound of Formula I, wherein X³ isCH

The application provides the above compound of Formula I, wherein X² isN.

The application provides the above compound of Formula I, wherein R¹ is—C(═O)R^(1′) and R′ is morpholine.

The application provides the above compound of Formula I, wherein n is1.

The application provides the above compound of Formula I, wherein X isCH or CH₂.

The application provides the above compound of Formula I, wherein Y isCH or CH₂.

The application provides a compound of Formula I, wherein n is 2 and Yis O.

The application provides a compound of Formula I, wherein n is 2, Y isO, R² is H, R³ is tert-butyl, X³ is CH, and X² is N.

The application provides the above compound of Formula I, wherein R¹ is—S(═O)₂R″ and R′ is methyl or R¹ is —C(═O)R^(1′) and R′ is morpholine.

The application provides a compound of Formula I, selected from thegroup consisting of:

-   2-[2-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)pyridin-2-yl]amino]-6-oxopyridazin-3-yl]phenyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-2-methylpropanenitrile;-   2-[8-fluoro-2-[2-(hydroxymethyl)-3-[5-[[5-(1-hydroxy-2-methylpropan-2-yl)oxypyridin-2-yl]amino]-1-methyl-6-oxopyridazin-3-yl]phenyl]-1-oxoisoquinolin-6-yl]-2-methylpropanenitrile;-   4-[2-(hydroxymethyl)-3-[1-methyl-5-[(5-methylsulfonylpyridin-2-yl)amino]-6-oxopyridazin-3-yl]phenyl]-8-(1-hydroxy-2-methylpropan-2-yl)-2,3-dihydro-1,4-benzoxazepin-5-one;-   5-chloro-N-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)pyridin-2-yl]amino]-6-oxopyridin-3-yl]phenyl]-1,3-dihydroisoindole-2-carboxamide;-   6-tert-butyl-2-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)pyridin-2-yl]amino]-6-oxopyridin-3-yl]phenyl]-3,4-dihydro-2,7-naphthyridin-1-one;-   6-tert-butyl-2-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)pyridin-2-yl]amino]-6-oxopyridazin-3-yl]phenyl]-3,4-dihydro-2,7-naphthyridin-1-one;-   6-tert-butyl-8-fluoro-2-[2-methyl-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)pyridin-2-yl]amino]-6-oxopyridazin-3-yl]phenyl]phthalazin-1-one;-   8-tert-butyl-4-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)pyridin-2-yl]amino]-6-oxopyridazin-3-yl]phenyl]-2,3-dihydro-1,4-benzoxazepin-5-one;    and-   8-tert-butyl-4-[2-(hydroxymethyl)-3-[1-methyl-5-[(5-methylsulfonylpyridin-2-yl)amino]-6-oxopyridazin-3-yl]phenyl]-2,3-dihydro-1,4-benzoxazepin-5-one.

The application provides a method for treating an inflammatory and/orautoimmune condition comprising administering to a patient in needthereof a therapeutically effective amount of the compound of Formula I.

The application provides a method for treating rheumatoid arthritiscomprising administering to a patient in need thereof a therapeuticallyeffective amount of the compound of Formula I.

The application provides a method for treating asthma comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the compound of Formula I.

The application provides a pharmaceutical composition comprising thecompound of Formula I.

The application provides a pharmaceutical composition comprising thecompound of Formula I, admixed with at least one pharmaceuticallyacceptable carrier, excipient or diluent.

The application provides a use of the compound of formula I in themanufacture of a medicament for the treatment of an inflammatorydisorder.

The application provides a use of the compound of formula I in themanufacture of a medicament for the treatment of an autoimmune disorder.

The application provides a use of the compound of formula I in themanufacture of a medicament for the treatment of rheumatoid arthritis.

The application provides a use of the compound of formula I in themanufacture of a medicament for the treatment of asthma.

The application provides the use of a compound as described above forthe treatment of inflammatory and/or autoimmune condition.

The application provides the use of a compound as described above forthe treatment of rheumatoid arthritis.

The application provides the use of a compound as described above forthe treatment of asthma.

The application provides a compound, method, or composition as describedherein.

Compounds and Preparation

Examples of representative compounds encompassed by the presentinvention and within the scope of the invention are provided in thefollowing Table. These examples and preparations which follow areprovided to enable those skilled in the art to more clearly understandand to practice the present invention. They should not be considered aslimiting the scope of the invention, but merely as being illustrativeand representative thereof.

In general, the nomenclature used in this Application is based onAUTONOMTM v.4.0, a Beilstein Institute computerized system for thegeneration of IUPAC systematic nomenclature. If there is a discrepancybetween a depicted structure and a name given that structure, thedepicted structure is to be accorded more weight. In addition, if thestereochemistry of a structure or a portion of a structure is notindicated with, for example, bold or dashed lines, the structure orportion of the structure is to be interpreted as encompassing allstereoisomers of it.

TABLE I depicts examples of compounds according to generic Formula I.These compounds were designed to contain a more polar (cLogP<2)selectivity group (for example, where the tert-butyl benzamide islocated) combined with a pyridazinone core group to minimize livertoxicity found with similar compounds that do not contain thisbenefitial combination.

TABLE I Compound Nomenclature Structure 1 2-[2-[2- (hydroxymethyl)-3-[1-methyl-5-[[5- (morpholine-4- carbonyl)pyridin-2- yl]amino]-6-oxopyridazin-3- yl]phenyl]-1-oxo-3,4- dihydroisoquinolin-6- yl]-2-methylpropanenitrile

2 2-[8-fluoro-2-[2- (hydroxymethyl)-3-[5- [[5-(1-hydroxy-2-methylpropan-2- yl)oxypyridin-2- yl]amino]-1-methyl-6- oxopyridazin-3-yl]phenyl]-1- oxoisoquinolin-6-yl]- 2-methylpropanenitrile

3 4-[2- (hydroxymethyl)-3-[1- methyl-5-[(5- methylsulfonylpyridin-2-yl)amino]-6- oxopyridazin-3- yl]phenyl]-8-(1- hydroxy-2-methylpropan-2-yl)- 2,3-dihydro-1,4- benzoxazepin-5-one

4 5-chloro-N-[2- (hydroxymethyl)-3-[1- methyl-5-[[5- (morpholine-4-carbonyl)pyridin-2- yl]amino]-6- oxopyridin-3- yl]phenyl]-1,3-dihydroisoindole-2- carboxamide

5 6-tert-butyl-2-[2- (hydroxymethyl)-3-[1- methyl-5-[[5- (morpholine-4-carbonyl)pyridin-2- yl]amino]-6- oxopyridin-3- yl]phenyl]-3,4-dihydro-2,7- naphthyridin-1-one

6 6-tert-butyl-2-[2- (hydroxymethyl)-3-[1- methyl-5-[[5- (morpholine-4-carbonyl)pyridin-2- yl]amino]-6- oxopyridazin-3- yl]phenyl]-3,4-dihydro-2,7- naphthyridin-1-one

7 6-tert-butyl-8-fluoro- 2-[2-methyl-3-[1- methyl-5-[[5- (morpholine-4-carbonyl)pyridin-2- yl]amino]-6- oxopyridazin-3- yl]phenyl]phthalazin-1-one

8 8-tert-butyl-4-[2- (hydroxymethyl)-3-[1- methyl-5-[[5- (morpholine-4-carbonyl)pyridin-2- yl]amino]-6- oxopyridazin-3- yl]phenyl]-2,3-dihydro-1,4- benzoxazepin-5-one

9 8-tert-butyl-4-[2- (hydroxymethyl)-3-[1- methyl-5-[(5-methylsulfonylpyridin- 2-yl)amino]-6- oxopyridazin-3- yl]phenyl]-2,3-dihydro-1,4- benzoxazepin-5-one

General Synthetic Schemes

The compounds of the present invention may be prepared by anyconventional means. Suitable processes for synthesizing these compoundsare provided in the examples. Generally, compounds of the invention maybe prepared according to the schemes below.

5-Fluoro-indan-1-one 10 was subjected to a Schmidt reaction to afforddihydro-isoquinolinone 11, which was treated with excessisobutyronitrile potassium salt to furnish cyano compound 12.Buckwald-Hartwig coupling with dibromobenzaldehyde 13 gave mono-bromide14, which through a Suzuki coupling with the preformed boronate of 15afforded pyridazinone 16. Final reduction to the benzylic alcohol gavecompound of interest 1.

1-Bromo-3,5-difluorobenzene 17 was subjected to an aromatic nucleophilicsubstitution with the lithium salt of isobutyronitrile to affordselectively cyano compound 18, which was converted to its lithium saltwith lithium diisopropylamide and quenched with carbon dioxide tofurnish acid 19. After treatment with carbonyl diimidazole and ammoniumhydroxide amide 20 was obtained. Suzuki coupling with the ethoxy-vinylboronate 21, followed by acid treatment gave isoquinolinone 22, whichwas subjected to a nucleophilic aromatic substitution with2-bromo-6-fluoro-benzaldehyde and potassium carbonate to affordintermediate 23. On the other hand, 6-amino-pyridin-3-ol 24 wasalkylated with ethyl bromo-isobutyrate 25 to afford aromatic ether 26,which was subjected to a Buckwald-Hartwig coupling with thebromo-chloro-pyridazinone 27 to give 28. Reduction of ester with LAHafforded alcohol 29. Transformation of 29 to its boronate ester,followed by Suzuki coupling with bromide 23 furnished aldehyde 30, whichwas reduced to the corresponding alcohol to obtain compound of interest2.

O-methyl-2-chloro-benzaldoxime 32, obtained from chlorobenzaldehyde 31,was selectively ortho-brominated under Pd-catalyzed C—H activation (J.Org. Chem. 2011, 76, 6414-6420) to afford 33, which was hydrolyzed tointermediate 34. On the other hand, 5-bromo-pyridin-2-ylamine 35 wastreated with sodium methanesulfinate to give sulfone 36, which wascoupled with bromo-pyridazinone 27 to afford intermediate 37.p-Methoxybenzaldehyde 38 was reductively aminated to obtain aminoalcohol39, which was transformed to the amide 41 after condensation with4-bromo-2-fluorobenzoic acid 40. Intramolecular cyclization to thebenzo-oxazepinone 42 was achieved after treatment with sodium hydride.Palladium catalyzed condensation of isobutyraldehyde with 42 under basicconditions gave aldehyde 43. Debenzylation followed by Buckwald-Hartwigcoupling with intermediate 34 afforded bis-aldehyde 45. Suzuki couplingwith chloropyridazinone intermediate 37 gave 46, which was reduced toobtain the compound of interest 3.

Nitroalcohol 47 was O-protected and reduced to aniline 49, which wastransformed to boronate ester 50 and coupled with bromide 51 to afford52, which through its isocyanate was condensed with chloro-isoindoline53 to afford urea 54. Final deprotection gave compound of interest 4.

Nicotinamide 55 was treated with 2,2-dimethyl-propionic acid in thepresence of silver nitrate and ammonium persulfate to obtaintert-butylnicotinamide 56, which was treated with phthalimidopropanoicacid 57 in the presence again of silver nitrate and ammonium persulfateto afford 58 (Journal of Heterocyclic Chemistry 1989, 26, 45). Treatmentof 58 with hydrazine deprotected the phthalimide to afford afterintramolecular cyclization the dihydro-naphthyridinone 59, which wascoupled with dibromobenzaldehyde 13 under Buckwald-Hartwig conditions tofurnish bromide 60. Suzuki coupling with the halide 61 gave 62, whichafter reduction gave compounds of interest 5 and 6.

Fluorophthalazinone 63 (US 20100222325 A1) was coupled withdibromotoluene 64 under palladium (0) conditions to afford monobromide65, which was transformed to the boronate ester 66 and coupled with 15under Suzuki conditions to furnished compound of interest 7.

3-tert-Butylphenol 67 was alkylated with bromide 68 to afford aromaticether 69, which by acid treatment cyclized to chromanol 70. Oxidationwith PCC gave chromanone 71. Schmidt reaction with sodium azide andmethanesulfonic acid afforded dihydro-benzoxazepinone 72, which wassubjected to a Buckwald-Hartwig coupling with dibrobenzaldehyde 13 tofurnish bromide 73. Suzuki coupling with the correspondingchloropyridazinone 15 or 37 gave 74, which was reduced to compounds ofinterest 8 and 9.

Pharmaceutical Compositions and Administration

The compounds of the present invention may be formulated in a widevariety of oral administration dosage forms and carriers. Oraladministration can be in the form of tablets, coated tablets, dragées,hard and soft gelatin capsules, solutions, emulsions, syrups, orsuspensions. Compounds of the present invention are efficacious whenadministered by other routes of administration including continuous(intravenous drip) topical parenteral, intramuscular, intravenous,subcutaneous, transdermal (which may include a penetration enhancementagent), buccal, nasal, inhalation and suppository administration, amongother routes of administration. The preferred manner of administrationis generally oral using a convenient daily dosing regimen which can beadjusted according to the degree of affliction and the patient'sresponse to the active ingredient.

A compound or compounds of the present invention, as well as theirpharmaceutically useable salts, together with one or more conventionalexcipients, carriers, or diluents, may be placed into the form ofpharmaceutical compositions and unit dosages. The pharmaceuticalcompositions and unit dosage forms may be comprised of conventionalingredients in conventional proportions, with or without additionalactive compounds or principles, and the unit dosage forms may containany suitable effective amount of the active ingredient commensurate withthe intended daily dosage range to be employed. The pharmaceuticalcompositions may be employed as solids, such as tablets or filledcapsules, semisolids, powders, sustained release formulations, orliquids such as solutions, suspensions, emulsions, elixirs, or filledcapsules for oral use; or in the form of suppositories for rectal orvaginal administration; or in the form of sterile injectable solutionsfor parenteral use. A typical preparation will contain from about 5% toabout 95% active compound or compounds (w/w). The term “preparation” or“dosage form” is intended to include both solid and liquid formulationsof the active compound and one skilled in the art will appreciate thatan active ingredient can exist in different preparations depending onthe target organ or tissue and on the desired dose and pharmacokineticparameters.

The term “excipient” as used herein refers to a compound that is usefulin preparing a pharmaceutical composition, generally safe, non-toxic andneither biologically nor otherwise undesirable, and includes excipientsthat are acceptable for veterinary use as well as human pharmaceuticaluse. The compounds of this invention can be administered alone but willgenerally be administered in admixture with one or more suitablepharmaceutical excipients, diluents or carriers selected with regard tothe intended route of administration and standard pharmaceuticalpractice.

“Pharmaceutically acceptable” means that which is useful in preparing apharmaceutical composition that is generally safe, non-toxic, andneither biologically nor otherwise undesirable and includes that whichis acceptable for veterinary as well as human pharmaceutical use.

A “pharmaceutically acceptable salt” form of an active ingredient mayalso initially confer a desirable pharmacokinetic property on the activeingredient which were absent in the non-salt form, and may evenpositively affect the pharmacodynamics of the active ingredient withrespect to its therapeutic activity in the body. The phrase“pharmaceutically acceptable salt” of a compound means a salt that ispharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include: (1)acid addition salts, formed with inorganic acids such as hydrochloricacid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, andthe like; or formed with organic acids such as acetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvicacid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid,fumaric acid, tartaric acid, citric acid, benzoic acid,3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid,2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid,4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like; or (2)salts formed when an acidic proton present in the parent compound eitheris replaced by a metal ion, e.g., an alkali metal ion, an alkaline earthion, or an aluminum ion; or coordinates with an organic base such asethanolamine, diethanolamine, triethanolamine, tromethamine,N-methylglucamine, and the like.

Solid form preparations include powders, tablets, pills, capsules,cachets, suppositories, and dispersible granules. A solid carrier may beone or more substances which may also act as diluents, flavoring agents,solubilizers, lubricants, suspending agents, binders, preservatives,tablet disintegrating agents, or an encapsulating material. In powders,the carrier generally is a finely divided solid which is a mixture withthe finely divided active component. In tablets, the active componentgenerally is mixed with the carrier having the necessary bindingcapacity in suitable proportions and compacted in the shape and sizedesired. Suitable carriers include but are not limited to magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.Solid form preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

Liquid formulations also are suitable for oral administration includeliquid formulation including emulsions, syrups, elixirs, aqueoussolutions, aqueous suspensions. These include solid form preparationswhich are intended to be converted to liquid form preparations shortlybefore use. Emulsions may be prepared in solutions, for example, inaqueous propylene glycol solutions or may contain emulsifying agentssuch as lecithin, sorbitan monooleate, or acacia. Aqueous solutions canbe prepared by dissolving the active component in water and addingsuitable colorants, flavors, stabilizing, and thickening agents. Aqueoussuspensions can be prepared by dispersing the finely divided activecomponent in water with viscous material, such as natural or syntheticgums, resins, methylcellulose, sodium carboxymethylcellulose, and otherwell known suspending agents.

The compounds of the present invention may be formulated for parenteraladministration (e.g., by injection, for example bolus injection orcontinuous infusion) and may be presented in unit dose form in ampoules,pre-filled syringes, small volume infusion or in multi-dose containerswith an added preservative. The compositions may take such forms assuspensions, solutions, or emulsions in oily or aqueous vehicles, forexample solutions in aqueous polyethylene glycol. Examples of oily ornonaqueous carriers, diluents, solvents or vehicles include propyleneglycol, polyethylene glycol, vegetable oils (e.g., olive oil), andinjectable organic esters (e.g., ethyl oleate), and may containformulatory agents such as preserving, wetting, emulsifying orsuspending, stabilizing and/or dispersing agents. Alternatively, theactive ingredient may be in powder form, obtained by aseptic isolationof sterile solid or by lyophilization from solution for constitutionbefore use with a suitable vehicle, e.g., sterile, pyrogen-free water.

The compounds of the present invention may be formulated for topicaladministration to the epidermis as ointments, creams or lotions, or as atransdermal patch. Ointments and creams may, for example, be formulatedwith an aqueous or oily base with the addition of suitable thickeningand/or gelling agents. Lotions may be formulated with an aqueous or oilybase and will in general also containing one or more emulsifying agents,stabilizing agents, dispersing agents, suspending agents, thickeningagents, or coloring agents. Formulations suitable for topicaladministration in the mouth include lozenges comprising active agents ina flavored base, usually sucrose and acacia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatin andglycerin or sucrose and acacia; and mouthwashes comprising the activeingredient in a suitable liquid carrier.

The compounds of the present invention may be formulated foradministration as suppositories. A low melting wax, such as a mixture offatty acid glycerides or cocoa butter is first melted and the activecomponent is dispersed homogeneously, for example, by stirring. Themolten homogeneous mixture is then poured into convenient sized molds,allowed to cool, and to solidify.

The compounds of the present invention may be formulated for vaginaladministration. Pessaries, tampons, creams, gels, pastes, foams orsprays containing in addition to the active ingredient such carriers asare known in the art to be appropriate.

The compounds of the present invention may be formulated for nasaladministration. The solutions or suspensions are applied directly to thenasal cavity by conventional means, for example, with a dropper, pipetteor spray. The formulations may be provided in a single or multidoseform. In the latter case of a dropper or pipette, this may be achievedby the patient administering an appropriate, predetermined volume of thesolution or suspension. In the case of a spray, this may be achieved forexample by means of a metering atomizing spray pump.

The compounds of the present invention may be formulated for aerosoladministration, particularly to the respiratory tract and includingintranasal administration. The compound will generally have a smallparticle size for example of the order of five (5) microns or less. Sucha particle size may be obtained by means known in the art, for exampleby micronization. The active ingredient is provided in a pressurizedpack with a suitable propellant such as a chlorofluorocarbon (CFC), forexample, dichlorodifluoromethane, trichlorofluoromethane, ordichlorotetrafluoroethane, or carbon dioxide or other suitable gas. Theaerosol may conveniently also contain a surfactant such as lecithin. Thedose of drug may be controlled by a metered valve. Alternatively theactive ingredients may be provided in a form of a dry powder, forexample a powder mix of the compound in a suitable powder base such aslactose, starch, starch derivatives such as hydroxypropylmethylcellulose and polyvinylpyrrolidine (PVP). The powder carrier will form agel in the nasal cavity. The powder composition may be presented in unitdose form for example in capsules or cartridges of e.g., gelatin orblister packs from which the powder may be administered by means of aninhaler.

When desired, formulations can be prepared with enteric coatings adaptedfor sustained or controlled release administration of the activeingredient. For example, the compounds of the present invention can beformulated in transdermal or subcutaneous drug delivery devices. Thesedelivery systems are advantageous when sustained release of the compoundis necessary and when patient compliance with a treatment regimen iscrucial. Compounds in transdermal delivery systems are frequentlyattached to an skin-adhesive solid support. The compound of interest canalso be combined with a penetration enhancer, e.g., Azone(1-dodecylaza-cycloheptan-2-one). Sustained release delivery systems areinserted subcutaneously into to the subdermal layer by surgery orinjection. The subdermal implants encapsulate the compound in a lipidsoluble membrane, e.g., silicone rubber, or a biodegradable polymer,e.g., polyactic acid.

Suitable formulations along with pharmaceutical carriers, diluents andexcipients are described in Remington: The Science and Practice ofPharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19thedition, Easton, Pa. A skilled formulation scientist may modify theformulations within the teachings of the specification to providenumerous formulations for a particular route of administration withoutrendering the compositions of the present invention unstable orcompromising their therapeutic activity.

The modification of the present compounds to render them more soluble inwater or other vehicle, for example, may be easily accomplished by minormodifications (salt formulation, esterification, etc.), which are wellwithin the ordinary skill in the art. It is also well within theordinary skill of the art to modify the route of administration anddosage regimen of a particular compound in order to manage thepharmacokinetics of the present compounds for maximum beneficial effectin patients.

The term “therapeutically effective amount” as used herein means anamount required to reduce symptoms of the disease in an individual. Thedose will be adjusted to the individual requirements in each particularcase. That dosage can vary within wide limits depending upon numerousfactors such as the severity of the disease to be treated, the age andgeneral health condition of the patient, other medicaments with whichthe patient is being treated, the route and form of administration andthe preferences and experience of the medical practitioner involved. Fororal administration, a daily dosage of between about 0.01 and about 1000mg/kg body weight per day should be appropriate in monotherapy and/or incombination therapy. A preferred daily dosage is between about 0.1 andabout 500 mg/kg body weight, more preferred 0.1 and about 100 mg/kg bodyweight and most preferred 1.0 and about 10 mg/kg body weight per day.Thus, for administration to a 70 kg person, the dosage range would beabout 7 mg to 0.7 g per day. The daily dosage can be administered as asingle dosage or in divided dosages, typically between 1 and 5 dosagesper day. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect for theindividual patient is reached. One of ordinary skill in treatingdiseases described herein will be able, without undue experimentationand in reliance on personal knowledge, experience and the disclosures ofthis application, to ascertain a therapeutically effective amount of thecompounds of the present invention for a given disease and patient.

The pharmaceutical preparations are preferably in unit dosage forms. Insuch form, the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

Indications and Methods of Treatment

The compounds of generic Formula I inhibit Bruton's tyrosine kinase(BTK). Activation of BTK by upstream kinases results in activation ofphospholipase-Cγ which, in turn, stimulates release of pro-inflammatorymediators. Compounds of Formula I are useful in the treatment ofarthritis and other anti-inflammatory and auto-immune diseases.Compounds according to Formula I are, accordingly, useful for thetreatment of arthritis. Compounds of Formula I are useful for inhibitingBTK in cells and for modulating B-cell development. The presentinvention further comprises pharmaceutical compositions containingcompounds of Formula I admixed with pharmaceutically acceptable carrier,excipients or diluents.

The compounds described herein are kinase inhibitors, in particular BTKinhibitors. These inhibitors can be useful for treating one or morediseases responsive to kinase inhibition, including diseases responsiveto BTK inhibition and/or inhibition of B-cell proliferation, in mammals.Without wishing to be bound to any particular theory, it is believedthat the interaction of the compounds of the invention with BTK resultsin the inhibition of BTK activity and thus in the pharmaceutical utilityof these compounds. Accordingly, the invention includes a method oftreating a mammal, for instance a human, having a disease responsive toinhibition of BTK activity, and/or inhibiting B-cell proliferation,comprising administrating to the mammal having such a disease, aneffective amount of at least one chemical entity provided herein. Aneffective concentration may be ascertained experimentally, for exampleby assaying blood concentration of the compound, or theoretically, bycalculating bioavailability. Other kinases that may be affected inaddition to BTK include, but are not limited to, other tyrosine kinasesand serine/threonine kinases.

Kinases play notable roles in signaling pathways controlling fundamentalcellular processes such as proliferation, differentiation, and death(apoptosis). Abnormal kinase activity has been implicated in a widerange of diseases, including multiple cancers, autoimmune and/orinflammatory diseases, and acute inflammatory reactions. Themultifaceted role of kinases in key cell signaling pathways provides asignificant opportunity to identify novel drugs targeting kinases andsignaling pathways.

An embodiment includes a method of treating a patient having anautoimmune and/or inflammatory disease, or an acute inflammatoryreaction responsive to inhibition of BTK activity and/or B-cellproliferation.

Autoimmune and/or inflammatory diseases that can be affected usingcompounds and compositions according to the invention include, but arenot limited to: psoriasis, allergy, Crohn's disease, irritable bowelsyndrome, Sjogren's disease, tissue graft rejection, and hyperacuterejection of transplanted organs, asthma, systemic lupus erythematosus(and associated glomerulonephritis), dermatomyositis, multiplesclerosis, scleroderma, vasculitis (ANCA-associated and othervasculitides), autoimmune hemolytic and thrombocytopenic states,Goodpasture's syndrome (and associated glomerulonephritis and pulmonaryhemorrhage), atherosclerosis, rheumatoid arthritis, chronic Idiopathicthrombocytopenic purpura (ITP), Addison's disease, Parkinson's disease,Alzheimer's disease, diabetes, septic shock, and myasthenia gravis.

Included herein are methods of treatment in which at least one chemicalentity provided herein is administered in combination with ananti-inflammatory agent. Anti-inflammatory agents include but are notlimited to NSAIDs, non-specific and COX-2 specific cyclooxgenase enzymeinhibitors, gold compounds, corticosteroids, methotrexate, tumornecrosis factor receptor (TNF) receptors antagonists, immunosuppressantsand methotrexate.

Examples of NSAIDs include, but are not limited to, ibuprofen,flurbiprofen, naproxen and naproxen sodium, diclofenac, combinations ofdiclofenac sodium and misoprostol, sulindac, oxaprozin, diflunisal,piroxicam, indomethacin, etodolac, fenoprofen calcium, ketoprofen,sodium nabumetone, sulfasalazine, tolmetin sodium, andhydroxychloroquine. Examples of NSAIDs also include COX-2 specificinhibitors such as celecoxib, valdecoxib, lumiracoxib and/or etoricoxib.

In some embodiments, the anti-inflammatory agent is a salicylate.Salicylates include by are not limited to acetylsalicylic acid oraspirin, sodium salicylate, and choline and magnesium salicylates.

The anti-inflammatory agent may also be a corticosteroid. For example,the corticosteroid may be cortisone, dexamethasone, methylprednisolone,prednisolone, prednisolone sodium phosphate, or prednisone.

In additional embodiments the anti-inflammatory agent is a gold compoundsuch as gold sodium thiomalate or auranofin.

The invention also includes embodiments in which the anti-inflammatoryagent is a metabolic inhibitor such as a dihydrofolate reductaseinhibitor, such as methotrexate or a dihydroorotate dehydrogenaseinhibitor, such as leflunomide.

Other embodiments of the invention pertain to combinations in which atleast one anti-inflammatory compound is an anti-C5 monoclonal antibody(such as eculizumab or pexelizumab), a TNF antagonist, such asentanercept, or infliximab, which is an anti-TNF alpha monoclonalantibody.

Still other embodiments of the invention pertain to combinations inwhich at least one active agent is an immunosuppressant compound such asan immunosuppressant compound chosen from methotrexate, leflunomide,cyclosporine, tacrolimus, azathioprine, and mycophenolate mofetil.

B-cells and B-cell precursors expressing BTK have been implicated in thepathology of B-cell malignancies, including, but not limited to, B-celllymphoma, lymphoma (including Hodgkin's and non-Hodgkin's lymphoma),hairy cell lymphoma, multiple myeloma, chronic and acute myelogenousleukemia and chronic and acute lymphocytic leukemia.

BTK has been shown to be an inhibitor of the Fas/APO-1 (CD-95) deathinducing signaling complex (DISC) in B-lineage lymphoid cells. The fateof leukemia/lymphoma cells may reside in the balance between theopposing proapoptotic effects of caspases activated by DISC and anupstream anti-apoptotic regulatory mechanism involving BTK and/or itssubstrates (Vassilev et al., J. Biol. Chem. 1998, 274, 1646-1656).

It has also been discovered that BTK inhibitors are useful aschemosensitizing agents, and, thus, are useful in combination with otherchemotherapeutic drugs, in particular, drugs that induce apoptosis.Examples of other chemotherapeutic drugs that can be used in combinationwith chemosensitizing BTK inhibitors include topoisomerase I inhibitors(camptothecin or topotecan), topoisomerase II inhibitors (e.g.daunomycin and etoposide), alkylating agents (e.g. cyclophosphamide,melphalan and BCNU), tubulin directed agents (e.g. taxol andvinblastine), and biological agents (e.g. antibodies such as anti CD20antibody, IDEC 8, immunotoxins, and cytokines).

BTK activity has also be associated with some leukemias expressing thebcr-abl fusion gene resulting from translocation of parts of chromosome9 and 22. This abnormality is commonly observed in chronic myelogenousleukemia. BTK is constitutively phosphorylated by the bcr-abl kinasewhich initiates downstream survival signals which circumvents apoptosisin bcr-abl cells. (N. Feldhahn et al. J. Exp. Med. 2005201(11):1837-1852).

Methods of Treatment

The application provides a method for treating an inflammatory and/orautoimmune condition comprising administering to a patient in needthereof a therapeutically effective amount of the compound of Formula I.

The application provides a method for treating an inflammatory conditioncomprising administering to a patient in need thereof a therapeuticallyeffective amount of the compound of Formula I.

The application provides a method for treating rheumatoid arthritiscomprising administering to a patient in need thereof a therapeuticallyeffective amount of the compound of Formula I.

The application provides a method for treating asthma comprisingadministering to a patient in need thereof a therapeutically effectiveamount of Formula I.

The application provides a method for treating an inflammatory and/orautoimmune condition comprising administering to a patient in needthereof a therapeutically effective amount of the BTK inhibitor compoundof Formulae I.

The application provides a method for treating arthritis comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the BTK inhibitor compound of Formula I.

The application provides a method for treating asthma comprisingadministering to a patient in need thereof a therapeutically effectiveamount of the BTK inhibitor compound of Formula I.

The application provides a method of inhibiting B-cell proliferationcomprising administering to a patient in need thereof a therapeuticallyeffective amount of the BTK inhibitor compound of Formula I.

The application provides a method for inhibiting BTK activity comprisingadministering the BTK inhibitor compound of any one of Formula I,wherein the BTK inhibitor compound exhibits an IC₅₀ of 50 micromolar orless in an in vitro biochemical assay of BTK activity.

In one variation of the above method, the BTK inhibitor compoundexhibits an IC₅₀ of 100 nanomolar or less in an in vitro biochemicalassay of BTK activity.

In another variation of the above method, the compound exhibits an IC₅₀of 10 nanomolar or less in an in vitro biochemical assay of BTKactivity.

The application provides a method for treating an inflammatory conditioncomprising co-administering to a patient in need thereof atherapeutically effective amount of an anti-inflammatory compound incombination with the BTK inhibitor compound of Formula I.

The application provides a method for treating arthritis comprisingco-administering to a patient in need thereof a therapeuticallyeffective amount of an anti-inflammatory compound in combination withthe BTK inhibitor compound of Formula I.

The application provides a method for treating a lymphoma or a BCR-ABL1⁺leukemia cells by administering to a patient in need thereof atherapeutically effective amount of the BTK inhibitor compound ofFormula I.

The invention provides the use of a compound as described above for useas therapeutically active substance.

The invention provides the use of a compound as described above in thetreatment of an inflammatory and/or autoimmune condition.

The invention provides the use of a compound as described above for thepreparation of a medicament for the treatment of an inflammatory and/orautoimmune condition.

The invention provides a compound as described above for use in thetreatment of an inflammatory and/or autoimmune condition.

The invention provides a compound as described above for use in thetreatment of rheumatoid arthritis.

The invention provides a compound as described above for use in thetreatment of asthma.

The invention provides the invention as hereinbefore described.

EXAMPLES

General Abbreviations

Commonly used abbreviations include: acetyl (Ac),azo-bis-isobutyrylnitrile (AIBN), atmospheres (Atm),9-borabicyclo[3.3.1]nonane (9-BBN or BBN),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP), tert-butoxycarbonyl(Boc), di-tert-butyl pyrocarbonate or boc anhydride (BOC₂O), benzyl(Bn), butyl (Bu), Chemical Abstracts Registration Number (CASRN),benzyloxycarbonyl (CBZ or Z), carbonyl diimidazole (CDI),1,4-diazabicyclo[2.2.2]octane (DABCO), diethylaminosulfur trifluoride(DAST), dibenzylideneacetone (dba), 1,5-diazabicyclo[4.3.0]non-5-ene(DBN), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU),N,N′-dicyclohexylcarbodiimide (DCC), 1,2-dichloroethane (DCE),dichloromethane (DCM), 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (DDQ),diethyl azodicarboxylate (DEAD), di-iso-propylazodicarboxylate (DIAD),di-iso-butylaluminumhydride (DIBAL or DIBAL-H), di-iso-propylethylamine(DIPEA), N,N-dimethyl acetamide (DMA), 4-N,N-dimethylaminopyridine(DMAP), N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO),1,1′-bis-(diphenylphosphino)ethane (dppe),1,1′-bis-(diphenylphosphino)ferrocene (dppf),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI),2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), ethyl (Et), ethylacetate (EtOAc), ethanol (EtOH), 2-ethoxy-2H-quinoline-1-carboxylic acidethyl ester (EEDQ), diethyl ether (Et₂O), ethyl isopropyl ether(EtOiPr), O-(7-azabenzotriazole-1-yl)-N, N,N′N′-tetramethyluroniumhexafluorophosphate acetic acid (HATU), acetic acid (HOAc),1-N-hydroxybenzotriazole (HOBt), high pressure liquid chromatography(HPLC), iso-propanol (IPA), isopropylmagnesium chloride (iPrMgCl),hexamethyl disilazane (HMDS), liquid chromatography mass spectrometry(LCMS), lithium hexamethyl disilazane (LiHMDS), meta-chloroperoxybenzoicacid (m-CPBA), methanol (MeOH), melting point (mp), MeSO₂-(mesyl or Ms),methyl (Me), acetonitrile (MeCN), m-chloroperbenzoic acid (MCPBA), massspectrum (ms), methyl t-butyl ether (MTBE), methyl tetrahydrofuran(MeTHF), N-bromosuccinimide (NBS), n-Butyllithium (nBuLi),N-carboxyanhydride (NCA), N-chlorosuccinimide (NCS), N-methylmorpholine(NMM), N-methylpyrrolidone (NMP), pyridinium chlorochromate (PCC),Dichloro-((bis-diphenylphosphino)ferrocenyl) palladium(II)(Pd(dppf)Cl₂), palladium(II) acetate (Pd(OAc)₂),tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃), pyridiniumdichromate (PDC), phenyl (Ph), propyl (Pr), iso-propyl (i-Pr), poundsper square inch (psi), pyridine (pyr),1,2,3,4,5-Pentaphenyl-1′-(di-tert-butylphosphino)ferrocene (Q-Phos),room temperature (ambient temperature, rt or RT), sec-Butyllithium(sBuLi), tert-butyldimethylsilyl or t-BuMe₂Si (TBDMS),tetra-n-butylammonium fluoride (TBAF), triethylamine (TEA or Et₃N),2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO), trimethylsilylethoxymethyl(SEM), triflate or CF₃SO₂— (Tf), trifluoroacetic acid (TFA),1,1′-bis-2,2,6,6-tetramethylheptane-2,6-dione (TMHD),0-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU), thin layer chromatography (TLC), tetrahydrofuran (THF),trimethylsilyl or Me₃Si (TMS), p-toluenesulfonic acid monohydrate (TsOHor pTsOH), 4-Me-C₆H₄SO₂— or tosyl (Ts), andN-urethane-N-carboxyanhydride (UNCA). Conventional nomenclatureincluding the prefixes normal (n), iso (i-), secondary (sec-), tertiary(tert-) and neo have their customary meaning when used with an alkylmoiety. (J. Rigaudy and D. P. Klesney, Nomenclature in OrganicChemistry, IUPAC 1979 Pergamon Press, Oxford.).

General Conditions

Compounds of the present invention can be prepared beginning with thecommercially available starting materials by utilizing general synthetictechniques and procedures known to those skilled in the art. Outlinesbelow are reaction schemes suitable for preparing such compounds.Further exemplification can be found in the specific examples.

SPECIFIC ABBREVIATIONS

-   boc tert-butoxycarbonyl-   CH₂Cl₂ dichloromethane-   Cs₂CO₃ cesium carbonate-   DCM Dichloromethane-   DMF N,N-dimethylformamide-   DMSO Dimethylsulfoxide-   EtOAc ethyl acetate-   HATU    O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate-   Hunig's Base N,N-diisopropylethylamine-   HCl hydrogen chloride-   LC-MS liquid chromatography mass spectrometry-   HPLC high pressure liquid chromatography-   MeOH methyl alcohol-   MgSO₄ magnesium sulfate-   nBuLi n-butyl lithium-   NaCl sodium chloride-   Na₂CO₃ sodium carbonate-   NaOMe sodium methoxide-   Na₂SO₄ sodium sulfate-   NH₄OH ammonium hydroxide-   NMP 1-methyl-2-pyrrolidinone-   NMR nuclear magnetic resonance-   Pd(OAc)₂ palladium(II) acetate-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TLC thin layer chromatography-   TMSCl trimethylsilyl chloride    General Experimental Details

Reagents were purchased from Aldrich, Oakwood, Matrix or other suppliersand used without further purification. Reactions using microwaveirradiation for heating were conducted using either a Personal ChemistryEmrys Optimizer System or a CEM Discovery System. The purification ofmulti-milligram to multi-gram scale was conducted by methods known knowto those skilled in the art such as elution of silica gel flash column;preparative flash column purifications were also effected in some casesby use of disposal pre-packed multigram silica gel columns (RediSep)eluted with a CombiFlash system. Biotage™ and ISCO™ are also flashcolumn instruments that may have been used in this invention forpurification of intermediates.

For the purpose of judging compound identity and purity, LC/MS (liquidchromatography/mass spectroscopy) spectra were recorded using thefollowing system. For measurement of mass spectra, the system consistsof a Micromass Platform II spectrometer: ES Ionization in positive mode(mass range: 150-1200). The simultaneous chromatographic separation wasachieved with the following HPLC system: ES Industries Chromegabond WRC-18 3u 120 Å (3.2×30 mm) column cartridge; Mobile Phase A: Water (0.02%TFA) and Phase B: Acetonitrile (0.02% TFA); gradient 10% B to 90% B in 3minutes; equilibration time of 1 minute; flow rate of 2 mL/minute.

Many compounds of Formula 1 were also purified by reversed phased HPLC,using methods well known to those skilled in the art. In some cases,preparative HPLC purification was conducted using PE Sciex 150 EX MassSpec controlling a Gilson 215 collector attached to a Shimadzupreparative HPLC system and a Leap autoinjector. Compounds werecollected from the elution stream using LC/MS detection in the positiveion detection: The elution of compounds from C-18 columns (2.0×10 cmeluting at 20 mL/min) was effected using appropriate linear gradationmode over 10 minutes of Solvent (A) 0.05% TFA/H₂O and Solvent (B) 0.035%TFA/acetonitrile. For injection on to HPLC systems, the crude sampleswere dissolved in mixtures of methanol, acetonitrile and DMSO.

Compounds were characterized either by ¹H-NMR using a Bruker 400 MHz NMRSpectrometer.

The compounds of the present invention may be synthesized according toknown techniques. The following examples and references are provided toaid the understanding of the present invention. The examples are notintended, however, to limit the invention, the true scope of which isset forth in the appended claims. The names of the final products in theexamples were generated using Isis AutoNom 2000.

Preparative Examples

To a stirred solution of 5-fluoro-indan-1-one (15 g, 104.83 mmol) in DCM(168 mL) was added mesic acid (120 mL) at 0° C. To this clear solutionwas added sodium azide (9.5 g, 146.76 mmol) at −10° C. portion wise over40 min. The mixture was stirred for 2 h at −10° C., 20% aqueous NaOHsolution was added drop wise at 0° C., stirred for 15 min (TLC, silica;50% Ethyl acetate in hexane, R_(f)=0.3). After separating the DCM,aqueous part was extracted with DCM (2×50 mL), organic part was driedand concentrated, crude was purified by normal column chromatography(silica gel 100-200, product was eluted at 60% ethyl acetate in hexane)to get 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one (12.0 g, 69.31%) aswhite solid. LC-MS: 166.0 (M+H).

To a stirred solution of 6-fluoro-3,4-dihydro-2H-isoquinolin-1-one (2.5g, 15.14 mmol) in dry THF (30 mL) was added isobutyronitrile (3) (5.4mL, 60.54 mmol). To this solution was added 0.5 (M) KHMDS in toluene(104 ml, 52 mmol) slowly at 0° C., it was turned into yellowish viscousliquid. The mixture was heated at 70° C. for 4 h (monitored by LCMS).Cooled to RT 2^(nd) lot of isobutyronitrile (3 mL, 33.42 mmol) wasadded, again heated at 70° C. and stirred for 16 h (TLC, silica; 50%ethyl acetate in hexane, R_(f)=0.25). Reaction mixture was cooled;quenched with ice cold water (50 mL) and extracted with ethyl acetate(3×50 mL). Combined organic part was concentrated, obtained crude waspurified by CombiFlash column (40-60% ethyl acetate in hexane was usedas eluent) to get2-methyl-2-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-propionitrile(2.5 g, 77.09%) as white solid. LC-MS: 215.2 (M+H).

To a stirred solution of2-methyl-2-(1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl)-propionitrile(2.5 g, 11.68 mmol) in dry dioxane (50 mL) were added2,6-dibromo-benzaldehyde (4.6 g, 17.52 mmol), Cs₂CO₃ (7.6 g, 23.36mmol). The reaction mixture was degassed with argon, Pd(dba)2 (134 mg,0.234 mmol) and Xantphos (206 mg, 0.35 mmol) were added and againdegassed. The mixture was heated at 100° C. for 3 h, cooled to RT,filtered through a pad of celite; washed with ethyl acetate (3×50 mL).The mixture was concentrated and purified by CombiFlash column (elutedat 40% ethyl acetate in hexane) to get2-[2-(3-bromo-2-formyl-phenyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-2-methyl-propionitrile(2.5 g, 53.87%) as light brown solid. LC-MS: 397.2 (M+H).

The reaction mixture of6-chloro-2-methyl-4-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-2H-pyridazin-3-one(1.5 g, 4.29 mmol) (US2012/40949 A1), bis(pinacolato)diboron (1.4 g,5.57 mmol) and KOAc (dry) (1.3 g, 12.86 mmol) in dioxane (35 mL), wasdegassed under argon, X-Phos (307 mg, 0.64 mmol) and Pd(OAc)₂ (96 mg,0.43 mmol) were added and stirred at 98° C. for 15 min. The brownreaction mixture was turned greenish brown solution (monitored by LCMS).The flask was raised out of the heating bath, cooled, filtered through ashort plug of celite under argon into a second flask which contained adegassed suspension of2-[2-(3-bromo-2-formyl-phenyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-2-methyl-propionitrile(1.53 g, 3.86 mmol) and K₂CO₃ (2.37 g, 17.15 mmol) in dioxane-water(1:1; 90 mL), n-BuOH (10.5 mL). The reaction mixture was degassed withargon, ticyclohexylphosphine (359 mg, 1.28 mmol), and Pd(dba)2 (369 mg,0.642 mmol) were added, again degassed, and heated at 110° C. for 1 h.Reaction was cooled to RT, filtered through a plug of celite; washedwith ethylacetate (3×100 mL). Filtrate was concentrated, combined crudewas purified by normal column chromatography (normal silica gel 100-200mesh, eluted at 2 to 2.5% MeOH in DCM) to get2-[2-(2-formyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-yridazin-3-yl}-phenyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-2-methyl-propionitrileas light brown solid (1.5 g, 55.56%). LC-MS: 632.6 (M+H).

To a stirred solution of2-[2-(2-formyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-yridazin-3-yl}-phenyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-2-methyl-propionitrile(3 g, 4.75 mmol) in DCM (55 mL) and MeOH (36 mL) was added solution ofsodium borohydride (360 mg, 9.51 mmol) in water (3.6 mL) at 0° C. Thereaction mixture was stirred for 20 min at the same temperature.Reaction was monitored by TLC (Silica, UV/DNP, 5% MeOH in DCM, Rf=0.35).Reaction was quenched with ice, organic part was separated, dried andconcentrated). Crude was purified by normal silica gel columnchromatography (silica, 100-200, eluted at 2-2.5% MeOH in DCM). Purifiedmaterial was re-crystallized with DCM and hexane to get2-[2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2,3,4-tetrahydro-isoquinolin-6-yl]-2-methyl-propionitrileas white solid (2.1 g, 69.7%). LC-MS: 634.6 (M+H).

Charged 1-bromo-3,5-difluorobenzene (300 g, 1.55 mol, Eq: 1.00),isobutyronitrile (215 g, 3.11 mol, Eq: 2) and THF (1.2 l) into 5 L3-neck flask at room temperature. Added 1 M LiHMDS (1.71 l, 1.71 mol,Eq: 1.1) solution dropwise at temperature range 15-22° C. under coldwater bath; took 2.5 hr for addition. After 2.5 hr, conversion 91% byHPLC (9% SM and 12% dialkylated). Added additional 0.1 eq. of LiHMDSsolution. Stirred overnight when the conversion was 97% (3% SM and 21%dialkylated). Quenched reaction with 6N HCl to pH ˜3-4. Extracted withtoluene (twice); then the combined organics were concentrated down; usedmore toluene to remove water and also excess isobutyronitrile.Dialkylated byproduct was coming out during concentration; around 600 mLn-heptane was added, then stirred overnight at rt. Filtered the solutionto remove most of byproduct as solid; washed with heptane. Concentrateddown the filtrate to afford2-(3-bromo-5-fluorophenyl)-2-methylpropanenitrile (337.9 g, 1.26 mol,80.8% yield) with 90% HPLC purity (no SM and 9% dialkylated).

2-(3-bromo-5-fluorophenyl)-2-methylpropanenitrile (172 g, 710 mmol, Eq:1.00) was dissolved in THF (1.03 L), then the solution was cooled downto −75° C. Added 2M LDA (373 ml, 746 mmol, Eq: 1.05) into the solutiondropwise, and kept temperature below −70° C. Additional stirring for 2hr, and an aliquot was tested with dryice; full conversion. To another 3L rbf, dryice and THF were added. Reverse quenched with dryice; took 30min to transfer whole anion solution and kept temperature below −50° C.(−60˜−50° C.). Allowed to warm up to room temperature after additional 1hr stirring. Added water and acidified with 6 N HCl solution (pH 3-4).

Phase separation and extracted with MTBE and DCM. Concentrated thecombined organics. Obtained2-bromo-4-(2-cyanopropan-2-yl)-6-fluorobenzoic acid (246 g, 765 mmol,108% yield) as an oil (˜89% HPLC purity). No further purification andmoved on to the next reaction.

CDI (3.33 g, 20.6 mmol, Eq: 1.4) was added into a THF (42 ml) solutionof 2-bromo-4-(2-cyanopropan-2-yl)-6-fluorobenzoic acid (4.2 g, 14.7mmol, Eq: 1.00) portion-wise at room temperature. Stirred for 3 hr.Added ammonium hydroxide (17.1 g, 19.1 ml, 147 mmol, Eq: 10) to themixture. Stirred for 2 hr. Washed with 20% K₂CO₃ solution to removeunreacted starting material, then washed with 1 N HCl. Crystallizationfrom EtOAc/Heptane to give2-bromo-4-(2-cyanopropan-2-yl)-6-fluorobenzamide (3.4 g, 11.9 mmol,81.2% yield).

To a stirred solution of2-bromo-4(cyano-dimethyl-methyl)-6-fluoro-benzamide (2 g, 7.018 mmol)and 2-((E)-2-ethoxy-vinyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane(1.783 mL, 8.421 mmol) in dioxane-water (7:1; 16 mL) was added K₂CO₃(1.94 gm, 14.04 mmol) and followed by tricyclohexylphosphine (157 mg,0.561 mmol). The reaction mixture was well degassed with nitrogen. Tothis reaction mixture was added Pd(dba)2 (161 mg, 0.281 mmol), againdegassed with nitrogen and heated at 90° C. for 16 h and 6N HCl (6 mL)was added and heated to 40° C. for 5 h (silica TLC; 50% ethyl acetate inhexane, Rf=0.3). From the reaction mixture dioxane was removed underreduced pressure, obtained crude residue was purified by washings with10% EtOAc in hexane to get2-(8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile(1.26 g, 77.98%) as a brown solid. LC-MS: 229.2 (M−H).

To a stirred solution of2-(8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl)-2-methyl-propionitrile(1.26 gm, 5.478 mmol) in DMA (28 mL), was added2-bromo-6-fluoro-benzaldehyde (1.66 gm, 8.217 mmol), potassium carbonate(1.512 gm, 10.957 mmol) and followed by tetraethyl ammonium chloride(118 mg, 0.712 mmol) was added under argon. The reaction mixture heatedat 78° C. for 24 h (silica TLC; 50% ethyl acetate in hexane, Rf=0.50),water was added and extracted with DCM (2×90 mL). The combined extractwas concentrated to get crude product, which was purified by columnchromatography (normal silica gel 100-200 mesh; 25% EtOAc in hexane usedas eluent) to get2-[2-(3-bromo-2-formyl-phenyl)-8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile(840 mg, 37.11%) as a light yellow solid. LC/MC:

412.8 (M+), 414.8 (M+2).

The reaction mixture of6-chloro-4-[5-(2-hydroxy-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-2-methyl-2H-pyridazin-3-one(1 g, 3.08 mmol) (WO 2012020008 A1), bis(pinacolato)diboron (1.06 g,4.00 mmol) and KOAc (dry) (907 mg, 9.23 mmol) in dioxane (50 mL), wasdegassed under argon. X-Phos (220 mg, 0.46 mmol) and Pd(OAc)2 (69 mg,0.31 mmol) were added and stirred at 98° C. for 15 min (monitored byLCMS). The flask was raised out of the heating bath, cooled, filteredthrough a short plug of celite under argon into a second flask whichcontained a degassed suspension of2-[2-(3-bromo-2-formyl-phenyl)-8-fluoro-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile(1.14 g, 2.77 mmol) and K₂CO₃ (1.7 g, 12.31 mmol), dioxane (15.6 mL),water (15 mL), n-BuOH (3.7 mL). The reaction mixture was degassed withargon again and ticyclohexylphosphine (257 mg, 0.92 mmol), Pd(dba)₂ (264mg, 0.46 mmol) were added under inert atmosphere, the reaction mixturewas heated at 110° C. for 1 h. Reaction was cooled to RT, filteredthrough a plug of celite, washed with ethylacetate (3×100 mL). Combinedfiltrate was concentrated, obtained crude was purified by normal silicacolumn chromatography (silica gel 100-200 mesh, eluted at 2-2.5% MeOH inDCM) to get2-[8-fluoro-2-(2-formyl-3-{5-[5-(2-hydroxy-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile(1.1 g, 57.38%, 400 mg mixture) as brown sticky solid. LC-MS: 622.2(M+H).

To a stirred solution of2-[8-fluoro-2-(2-formyl-3-{5-[5-(2-hydroxy-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-1-oxo-1,2-dihydro-isoquinolin-6-yl]-2-methyl-propionitrile(2.4 g, 3.85 mmol) in DCM (46.7 mL) and MeOH (30.8 mL) was addedsolution of sodium borohydride (292 mg, 7.70 mmol) in water (3.4 mL) at0° C. The reaction mixture was stirred for 15 min at the sametemperature (Silica TLC; 5% MeOH in DCM, Rf=0.4). Reaction was quenchedwith ice (100 g), organic part was diluted with DCM (200 mL) andseparated, dried and concentrated. Obtained crude was purified by normalsilica column chromatography (silica, 100-200, eluted at 2% MeOH inDCM). Purified material was re-crystallized with DCM and ether to get2-[8-fluoro-2-(3-{5-[5-(2-hydroxy-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl}-2-hydroxymethyl-phenyl)-1-oxo-1,2-dihydro-soquinolin-6-yl]-2-methyl-propionitrile(1.6 g, 66.45%) as white solid. LC-MS: 625.3 (M+H).

To a stirred solution of 6-amino-pyridin-3-ol (4 gm, 36.364 mmol) in ACN(80 mL) was added cesium carbonate (47.41 gm, 145.45 mmol), stirred for1 h at RT, 2-bromo-2-methyl-propionic acid ethyl ester (5.66 gm, 38.18mmol) was added and stirred for 16 h (silica TLC; 50% EtOAc in hexane,Rf=0.5). To the reaction water (200 mL) was added and extracted withethyl acetate (3×100 mL). Combined extracts was concentrated, obtainedcrude was purified by column chromatography (normal silica gel 100-200mesh, 18 to 22% EtOAc in hexane was used as eluent) to get2-(6-amino-pyridin-3-yloxy)-2-methyl-propionic acid ethyl ester (4.4 g,53.96%) as a light yellow solid, LC/MS: 224.8 (M+H).

To a stirred solution of 2-(6-amino-pyridin-3-yloxy)-2-methyl-propionicacid ethyl ester (2 g, 8.929 mmol) and4-bromo-6-chloro-2-methyl-2H-pyridazin-3-one (2.588 gm, 11.607 mmol) indry dioxane (80 mL) was added Cs₂CO₃ (10.188 gm, 31.25 mmol). Thereaction mixture was well degassed with argon, xantphos (774 mg, 1.339mmol) and Pd₂(dba)₃ (654 mg, 0.714 mmol) were added under argonatmosphere, heated at 90° C. for 18 h. Cooled the reaction mixture,filtered through a plug of celite; washed with dioxane (50 mL). Combinedextracts was concentrated to get the crude, which was purified by normalsilica gel column chromatography using 18% EtOAc in hexane as eluent toget2-[6-(6-chloro-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino)-pyridin-3-yloxy]-2-methyl-propionicacid ethyl ester (2.7 gm, 82.44%) as a yellow solid, LC-MS: 367.0 (M+H).

To a stirred solution of2-[6-(6-chloro-2-methyl-3-oxo-2,3-dihydro-pyridazin-4-ylamino)-pyridin-3-yloxy]-2-methyl-propionicacid ethyl ester (1 g, 2.73 mmol) in dry THF (25 mL) was added LAH [3.8mL, 3.8 mmol, 1(M) solution in THF] drop wise (over 15 min via syringe)at −40° C. The reaction mixture was stirred for 1 h at the sametemperature (silica TLC; 50% EtOAc in hexane used as eluent; Rf=0.2).quench by adding water (0.1 mL), stirred for 10 min, added 5% NaOHsolution (0.2 mL), stirred for 10 min, again added water (0.2 mL),stirred for 10 min, clear organic part was separated, dried andconcentrated, crude was purified by normal silica column chromatography(silica gel 100-200 mesh, eluted at 40-50% ethyl acetate in hexane) toget6-chloro-4-[5-(2-hydroxy-1,1-dimethyl-ethoxy)-pyridin-2-ylamino]-2-methyl-2H-pyridazin-3-oneas off white solid (650 mg, 73.42%). LC-MS: 325.2 (M+H).

To a stirred solution of 4-methoxybenzaldehyde (20 g, 147.05 mmol) inmethanol (150 mL), was added amino ethanol (35.88 g, 588.23 mmol),acetic acid (40.58 g, 676.47 mmol) and stirred at RT for 20 h, toreaction sodium cyanoborohydride (5.54 g, 88.23 mmol) was added andstirred at RT for 36 h (silica TLC; 5% MeOH in DCM used as eluent;Rf=0.2). To the reaction mixture saturated NaHCO₃ in water (500 mL) wasadded and extracted with EtOAc (3×300 mL). Combined extracts was dried,concentrated under vacuum to get 2-(4-methoxy-benzylamino)-ethanol (6.0g, 22.51%) as reddish oil LC-MS: 182.2 (M+H).

To a stirred solution of, 2-(4-methoxybenzylamino)ethanol (1.0 g, 5.52mmol) in DCM (20 mL), were added 4-bromo-2-fluorobenzoic acid (1.21 g,5.52), DIPEA (1.18 mL, 7.18 mmol) and HATU (2.1 g, 5.52 mmol), stirredat RT for 16 h (silica TLC; 5% MeOH in DCM as mobile phase; Rf=0.5).Reaction mixture was concentrated; to the residue, saturated aqueousNH₄Cl (50 mL) was added and extracted with EtOAc (3×20 mL). Combinedorganic phase was washed with 1% aqueous HCl (30 mL) and water (20 mL).Separated organic part was dried, concentrated to get the crude mass,which was purified by flash chromatography (silica gel, eluted with 40%EtOAc in hexane), to get4-bromo-2-fluoro-N-(2-hydroxy-ethyl)-N-(4-methoxy-benzyl)-benzamide (0.5g, 23.68%) as yellow liquid. LC-MS: 382.2 (M+), 384.2 (M+2).

To a stirred solution of,4-bromo-2-fluoro-N-(2-hydroxyethyl)-N-(4-methoxybenzyl)-benzamide (1.0g, 2.61 mmol) in DMF (10 mL), was added NaH [(60% in paraffin oil);0.125 g, 3.14 mmol] at RT and stirred under argon for 16 h (silica TLC;50% EtOAc in hexane; Rf=0.5). To the reaction mixture aqueous saturatedNH₄Cl (30 mL) was added and extracted with EtOAc (3×25 mL). Combinedextracts was washed with water (50 mL) followed by brine (30 mL); driedand concentrated to get the crude mass, which was purified by flashchromatography (normal silica gel, 25% EtOAc in hexane used as eluent),to get8-bromo-4-(4-methoxy-benzyl)-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one(0.6 g, 63.28%) as white solid LC-MS: 362.2 (M+), 264.2 (M+2).

In a sealed tube,8-bromo-4-(4-methoxy-benzyl)-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one(2 g, 5.52 mmol), BINAP (0.206 g, 0.33 mmol) and Cs₂CO₃ (4.67 g, 14.36mmol) were taken in dioxane (35 mL). Reaction mixture was de-gassed withargon for 5 min, isobutyraldehyde (27) (1.03 g, 14.36 mmol) and Pd(OAc)₂(50 mg, 0.22 mmol) were added under argon atmosphere. Reaction mixturewas slowly heated to 80° C. and stirred for 16 h (silica TLC; 40%EtOAC/hexane; Rf=0.4). To the reaction mixture aqueous saturated NH4Cl(50 mL) was added at RT, and extracted with EtOAc (2×40 mL), combinedextracts was washed with water (50 mL), dried and concentrated. Obtainedcrude product mixture was purified by flash chromatography (normalsilica gel, 25% EtOAc in hexane used as mobile phase) to get pure2-[4-(4-methoxy-benzyl)-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-8-yl]-2-methyl-propionaldehyde(1.0 g, 51.22%) as white solid. LC-MS: 354.0 (M+H).

To a stirred solution of2-[4-(4-methoxy-benzyl)-5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-8-yl]-2-methyl-propionaldehyde(1.5 g, 4.24 mmol) in TFA (66.77 mL, 866.85 mmol) was taken in a sealedtube, reaction mixture was heated at 100° C. for 1 h (silica TLC; 60%EtOAc in hexane; Rf=0.2). Volatiles were removed under reduced pressure;residue was neutralized with aqueous saturated NaHCO₃ and extracted withEtOAc (2×200 mL). Combined extracts were dried, concentrated to get thecrude residue which was purified by flash chromatography (normal silicagel, 60% EtOAc in hexanes used as eluent) to get2-methyl-2-(5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-8-yl)-propionaldehyde(0.7 g, 70.6%) as white solid. LC-MS: 234.4 (M+H).

To a stirred solution of2-methyl-2-(5-oxo-2,3,4,5-tetrahydro-benzo[f][1,4]oxazepin-8-yl)-propionaldehyde(0.5 g, 2.14 mmol) and 2-bromo-6-chloro-benzaldehyde (30)(1.175 g, 5.36mmol) in dioxane (15 mL), Cs₂CO₃ (1.74 g, 5.36 mmol) was added anddegassed for 5 min with argon. To the degassed reaction mixture,Xantphos (0.124 g, 0.215 mmol) and Pd(dba)₂ (0.062 g, 0.107 mmol) wereadded under argon. Reaction was heated to 105 oC in sealed condition for6 h followed by 16 h at RT under stirring. Reaction mixture was dilutedwith EtOAc (300 mL) and washed with water (100 mL). Organic layer wasdried, concentrated under vacuum. Obtained crude residue was purified byflash chromatography (normal silica gel, 30% EtOAc in hexanes) to get2-chloro-6-[8-(1,1-dimethyl-2-oxo-ethyl)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-benzaldehyde(0.45 g, 56.4%) as Off white solid. LC-MS: 372.2 (M+), 374.2 (M+2).

To a stirred solution of6-chloro-4-(5-methanesulfonyl-pyridin-2-ylamino)-2-methyl-2H-pyridazin-3-one(0.75 g, 2.38 mmol), bis(pinacolato)diboron (1.2 g, 4.76 mmol), (X-phos)(0.17 g, 0.357 mmol) and KOAc (0.7 g, 7.14 mmol) were taken up in drydioxane (75 mL) and placed under vacuum and back-filled with argon. Tothis was added palladium acetate (0.053 g, 0.238 mmol) and the flask wasevacuated and back-filled with argon. The mixture was heated in an oilbath to 100° C. and stirred for 30 min (monitored by LCMS). A smallamount of des-Cl material was observed. Heating was turned down to 80°C. Flask was raised out of the heating bath but continued stirring, thefollowing reagents:2-chloro-6-[8-(1,1-dimethyl-2-oxo-ethyl)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-benzaldehyde(0.883 g, 2.38 mmol), K₂CO₃ (1.64 g, 11.90 mmol), water (5 mL; degassedseparately), tricyclohexylphosphine (200 mg, 0.71 mmol) and Pd(dba)2(205 mg, 0.36 mmol) was added. The flask was stirred and heated for 2 hat 80° C. and then cooled to RT. Poured in to water (100 mL) andextracted with EtOAc (3×150 mL), combined extracts was washed with brine(200 mL), aqueous part was re-extracted with 5% MeOH in DCM (200 mL).Both the organic extracts were combined, dried and concentrated underreduced pressure. Obtained crude was purified by flash chromatography(silica gel, 70% EtOAc in hexanes), to get2-[8-(1,1-dimethyl-2-oxo-ethyl)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-6-[5-(5-methanesulfonyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzaldehyde(0.55 g, 37.5%) as off white solid. LC-MS: 616.2 (M+H).

To a stirred solution of2-[8-(1,1-dimethyl-2-oxo-ethyl)-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl]-6-[5-(5-methanesulfonyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzaldehyde(2.5 g, 4.065 mmol) in methanol (90 mL) and dichloromethane (150 mL) wascooled in an ice bath. To this was added sodium borohydride (0.92 g,24.39 mmol). The mixture was stirred for 10 min (silica TLC; only EtOAcused as eluent; Rf=0.2), diluted with water (600 mL) and extracted withdichloromethane (2×600 mL). Combined organic layer was washed with brine(600 mL), dried concentrated under vacuum. Obtained residue was washedwith 80% EtOAc in hexane to get8-(2-hydroxy-1,1-dimethyl-ethyl)-4-{2-hydroxymethyl-3-[5-(5-methanesulfonyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl}-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one(2 g, 79.39%) as off white solid. LC-MS: 620.4 (M+H).

To a stirred solution of 2-chloro-benzaldehyde (10 g, 71.42 mmol) in DCM(220 mL), O-methyl-hydroxylamine hydrochloride (35) (7.11 g, 85.71 mmol)and pyridine (23 mL) were added. The reaction mixture was stirred for 1h at RT (silica TLC; 15% EtOAc in hexane; Rf=0.6). Reaction mixture wasconcentrated, obtained residue was purified by flash chromatographyusing 10% EtOAc in hexanes as eluent to get[(2-chlorophenyl)methylidene](methoxy)amine (9 g, 74.3%) as colorlessoil LC-MS: 170.4 (M+H).

In sealed tube [(2-chlorophenyl)methylidene](methoxy)amine (5 g, 29.58mmol) was taken in DCE (100 mL), followed by N-bromosuccinimide (5.23 g,29.58 mmol), silver trifluoroacetate (0.65 g, 2.95 mmol), palladiumacetate (0.66 g, 2.95 mmol) and acetic acid (1.77 g, 29.58 mmol) wereadded. The resulted mixture was heated to 120° C. for 24 h. At RT, water(150 mL) and DCM (300 mL) was added, and the mixture was filteredthrough a pad of celite. Organic layer was separated and the aqueouslayer was re-extracted with dichloromethane (200 mL). The combinedorganic layer was dried, concentrated, obtained crude mass was purifiedby flash chromatography using only hexane, to get[(2-bromo-6-chlorophenyl)methylidene](methoxy)amine (4.0 g, 54.4%) asyellow colored liquid.

In a sealed tube [(2-bromo-6-chlorophenyl)methylidene](methoxy)amine(4.0 g, 16.12 mmol) was taken in THF—H₂O (10:1; 110 mL). To the reactionmixture PTSA (6.12 g, 32.25 mmol) followed by para formaldehyde (4.83 g,161.29 mmol), was added and heated to 100° C. for 30 min (silica TLC;only hexane used as eluent; Rf=0.3). Reaction mixture was diluted withEtOAc (500 mL) and washed with water (200 mL). Organic layer was dried,concentrated under vacuum. Obtained crude residue was purified by flashchromatography using 5% EtOAc in hexanes as eluent to get2-bromo-6-chloro-benzaldehyde (3.0 g, 84.75%) as yellow solid.

In a round bottom flask under argon placed 5-bromo-pyridin-2-ylamine (10g, 57.8 mmol), sodium methanesulfinate (9.4 g, 92.48 mmol), copper (I)triflate-benzene complex (1.74 g, 3.468 mmol), racemic trans1,2-diaminocyclohexane (40) (1.41 mL, 11.742 mmol) and DMSO (50 mL).Reaction mixture was heated at 110° C. for 16 h. After completion of thereaction, mixture was poured into ice cooled water and aqueous wasextracted with EtOAc (3×100 mL). Combined organic layer was washed withsaturated brine solution, dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. Crude mass was purified over normal silica gelcolumn chromatography eluted with EtOAc-hexane to get5-methanesulfonyl-pyridin-2-ylamine as brown solid (4.0 g, 40.18%).

To a solution of 5-methanesulfonyl-pyridin-2-ylamine (1.9 g, 11.047mmol) in THF (40 mL) was added potassium tert-pentoxide (2M solution inTHF) (4.2 mL, 8.4 mmol) drop wise. The mixture was stirred for 10 min atRT, then cooled in an ice bath and4-bromo-6-chloro-2-methyl-2H-pyridazin-3-one (2.96 g, 13.256 mmol) wasdissolved in THF (20 mL) and added drop wise to the previous mixture.The whole mixture was again warmed to RT and stirred for 1.5 h. Aftercompletion of the reaction, it was quenched with 1M HCl and the mixturewas taken up in DCM and filtered through a sintered funnel. Filtrate waswashed with saturated brine solution, dried over anhydrous Na₂SO₄ andconcentrated under reduced pressure to get crude6-chloro-4-(5-methanesulfonyl-pyridin-2-ylamino)-2-methyl-2H-pyridazin-3-oneas off white solid (1.0 g, 28.76%), which was directly used for the nextstep without further purification.

To a solutions of (2-bromo-6-nitro-phenyl)-methanol (15.0 g, 64.65 mmol)in DCM (150 mL) were added sequentially tertiary butyl dimethyl sillylchloride (29.233 g, 193.94 mmol) and TEA (19.6 mL, 193.94 mmol). Theresulting mixture was stirred at 60° C. for 40 h. Reaction was monitoredby TLC (ethyl acetate:hexane=1:9; Rf=0.7). Solvent was removed underreduced pressure. The reaction mixture was partitioned between ethylacetate (1.5 L) and water (1.0 L). The organic layer was dried, filteredand concentrated. The crude was purified by silica gel (normal, 100-200mesh) column chromatography eluting with hexane to 5% ethyl acetate inhexane to get pure(2-bromo-6-nitro-benzyloxy)-tert-butyl-dimethyl-silane (21.0 gm, 93.81%)as light yellow liquid). LC-MS: 346.4 (M+), 348.4 (M+2).

A mixture of (2-bromo-6-nitro-benzyloxy)-tert-butyl-dimethyl-silane (7.0gm, 20.29 mmol), iron powder (3.83 gm, 68.58 mmol) and ammonium chloride(6.121 gm, 114.44 mmol) in ethanol-water (1:1; 340 mL) was heated at 90°C. for 4 h (silica TLC; ethyl acetate:hexane=1:19, Rf=0.4). The reactionmixture was filtered through a pad of celite in sintered funnel andwashed with ethyl acetate (2×20 mL). The combined filtrate and washingwas concentrated, ethyl acetate (1.5 L) was added to the crude andwashed with water (700 mL). The organic layer was dried, filtered andconcentrated, obtained crude was purified by neutral alumina columnchromatography eluting with hexane to 2% ethyl acetate in hexane to getpure 3-bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenylamine (5.8gm, 90.37%) as light orange liquid.

To a solution of3-bromo-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenylamine (1.0 gm,3.164 mmol) in dioxane (60.0 mL) were added4,4,5,5,4′,4′,5′,5′-octamethyl-[2,2′]bi[[1,3,2]dioxaborolanyl](4.018 gm,15.821 mmol) and KOAc (0.932 gm, 9.493 mmol). The mixture was degassedwith argon and to this mixture was added Pd(OAc)₂ (71 mg, 0.316 mmol)and X-Phos (211 mg, 0.443 mmol), degassing was continued with argon foranother 5 min then heated at 90° C. for 3 h (silica TLC; ethylacetate:hexane=1:19, Rf=0.4). Reaction mixture was filtered through apad of celite, washed with dioxane (2×5 mL) and combined with thefiltrate. Combined filtrates was concentrated under reduced pressure,obtained crude residue was purified by neutral alumina columnchromatography eluting with hexane to 2% ethyl acetate in hexane to getpure2-(tert-butyl-dimethyl-silanyloxymethyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(350 mg, 30.44%) as light orange solid. LC-MS: 364.2 (M+H).

To a stirred mixture of2-(tert-butyl-dimethyl-silanyloxymethyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine(1.3 g, 3.58 mmol) and5-bromo-1-methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one(1.407 g, 3.58 mmol) in dioxane (52.0 mL) in a sealed tube was added1(M) aqueous K₂CO₃ solution (10.7 mL) and degassed with argon. S-Phos(220 mg, 0.54 mmol) and Pd(PPh₃)₄ (207 mg, 0.18 mmol) were addedsubsequently and again degassed with argon; sealed and heated at 90° C.for 2.5 h (silica TLC; only ethyl acetate, Rf=0.5). Reaction mixture wascooled to RT and was added ethyl acetate (250 mL). The organic part waswashed with water (120 mL) and brine (120 mL), dried, filtered andconcentrated in vacuum to get crude mass which was purified by normalsilica gel (normal, 100-200 mesh) column chromatography using gradientpolarity eluent 50% ethyl acetate in hexane to pure ethyl acetate to getpure5-[3-amino-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-1-methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one(1.31 g, 66.61%) as off white solid. LC-MS: 550.4 (M+H).

To a solution of5-[3-amino-2-(tert-butyl-dimethyl-silanyloxymethyl)-phenyl]-1-methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one(700 mg, 1.27 mmol) in DCM (70.0 mL) was added triethylamine (0.44 mL,3.18 mmol) and cooled to 0° C. in a ice bath, followed by the additionof phosgene solution[0.8 mL, 1.53 mmol (20% in toluene)] and stirred for10 min at 0° C., followed by 5-chloro-2,3-dihydro-1H-isoindole (489 mg,3.18 mmol) was added and stirred for another 30 min (silica TLC; ethylacetate 100%, Rf=0.45). Solvent was removed under vacuum, obtained crudewas purified by silica gel (normal, 100-200 mesh) column chromatographyusing gradient eluent 50% ethyl acetate in hexane to 100% ethyl acetateto get 5-chloro-1,3-dihydro-isoindole-2-carboxylic acid(2-(tert-butyl-dimethyl-silanyloxymethyl)-3-[1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl]-phenyl)-amide(910 mg, 97.99%) as brown sticky solid. LC-MS: 729.4 (M+H).

To a solution of 5-chloro-1,3-dihydro-isoindole-2-carboxylic acid(2-(tert-butyl-dimethyl-silanyloxymethyl)-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-amide(900 mg, 1.23 mmol) in methanol (45.0 mL) and DCM (18.0 mL) was added12(N) HCl (0.9 mL) at RT and stirred for 10 min (silica TLC;methanol:DCM=1:19 used as eluent, Rf=0.4). Saturated NaHCO₃ solution wasadded drop wise till bubbling ceases. Reaction mass was diluted with DCM(600 mL) and washed with water (100 mL), brine (100 mL), dried andconcentrated in vacuum to get sticky crude mass which was purified byre-crystallization from DCM-hexane mixture to get pure5-chloro-1,3-dihydro-isoindole-2-carboxylic acid(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-amide(620 mg, 81.69%) as ash color solid. LC-MS: 615.2 (M+H).

To a stirred solution of nicotinamide (10.0 g, 81.88 mmol) in 10% H₂SO₄(82 mL), 2,2-dimethyl-propionic acid (41.8 g, 409.4 mmol) and AgNO₃ (4.2g, 24.564 mmol) were added and the mixture was heated at 70° C. withstirring. A solution of (NH₄)₂S₂O₈ (56.1 g, 245.64 mmol) in H₂O (122 mL)was added until the CO₂ evolution was ceased. Reaction was stirred for 1h more at the same temperature under argon atmosphere. After completionof the reaction, monitored by TLC, the mixture was cooled to RT,adjusted the pH˜9 by addition of aqueous NH₃ and extracted with EtOAc(3×200 mL). Combined organic layer was washed with water and brine,dried over anhydrous Na₂SO₄, concentrated under vacuum. The crudecompound was purified by CombiFlash column chromatography usingEtOAc-hexane as eluting solvent to get 6-tert-butyl-nicotinamide as offwhite solid (9.6 g, 66%). LCMS: 179.0 (M+H).

To a stirred solution of 6-tert-butyl-nicotinamide (2 g, 11.221 mmol) in10% H₂SO₄ (90 mL), 3-phthalimidopropanoic acid (9.84 g, 44.883 mmol),AgNO₃ (1.91 g, 11.221 mmol), (NH₄)₂S₂O₈ (20.5 g, 89.767 mmol) andcetyltrimethylammonium bromide (1.8 g, 4.937 mmol) were addedrespectively and the whole mixture was heated at 90° C. for 30 min. Thismixture was cooled to 70° C. and a solution of (NH₄)₂S₂O₈ (20.5 g,89.767 mmol) in ACN—H₂O(3:7) (100 mL) was added and the mixture wasagain heated at 90° C. for 3 h. Mixture was again cooled to 70° C. and asolution of (NH₄)₂S₂O₈ (20.5 g, 89.767 mmol) in ACN—H₂O(3:7) (100 mL)was added and kept at 90° C. for 16 h. RM was monitored by SiO₂ TLC, alittle SM was still present so the mixture was again cooled to 70° C.and a solution of (NH₄)₂S₂O₈ (20.5 g, 89.767 mmol) in ACN—H₂O(3:7) (100mL) was added and kept at 90° C. for another 6 h. Some amount startingmaterial was present in the mixture which was not consumed even afterprolonged heating. Reaction mixture was cooled to RT, neutralized topH˜7 by addition of aqueous NH₃ and extracted with DCM (2×300 mL).Combined organic layer was washed with water and brine, dried overanhydrous Na₂SO₄ and concentrated under vacuum to get crude mass, whichwas passed through a small bed of normal silica gel column to removeunwanted impurities to get6-tert-butyl-4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-nicotinamideas brown viscous oil (1.7 g crude) along with some other impurities.This impure material was directly used for the next step without furtherpurification. LCMS: 353.0 (M+H).

To a stirred solution of (2.55 g crude, 7.256 mmol) in CH₃CN (40 mL),NH₂NH₂.H₂O (0.68 mL, 14.513 mmol) was added and the mixture was refluxedfor 3 h. After completion of the reaction, monitored by SiO₂ TLC, themixture was cooled to RT, filtered through a sinter funnel and thefiltrate was concentrated under reduced pressure. The crude compound waspurified over normal silica gel column chromatography using EtOAc-hexaneas eluting solvent to get6-tert-butyl-3,4-dihydro-2H-[2,7]naphthyridin-1-one as off white solid(165 mg, 4.5% over 2 steps). LCMS: 205.0 (M+H).

6-tert-Butyl-3,4-dihydro-2H-[2,7]naphthyridin-1-one (0.46 g, 2.252mmol), 2,6-dibromo-benzaldehyde (2.97 g, 11.26 mmol), xanthphos (65.2mg, 0.113 mmol) and Cs₂CO₃ (1.03 g, 3.153 mmol) were taken up in1,4-dioxane (4.5 mL) and argon gas was bubbled through the mixture for10 min Pd(dba)₂ (38.8 mg, 0.068 mmol) was added to it and stirred at100° C. for 4 h. After completion of the reaction, (monitored by TLC),resultant mixture was cooled to RT and this was partitioned betweenEtOAc and water. Organic layer was collected and dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. Crude mass was purifiedover normal silica gel column chromatography using EtOAc-hexane to get2-bromo-6-(6-tert-butyl-1-oxo-3,4-dihydro-1H-[2,7]naphthyridin-2-yl)-benzaldehydeas off white solid (416.0 mg, 47.7%). LCMS: 387.0 (M) & 389.0 (M+2).

A solution of5-chloro-1-methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-1H-pyridin-2-one(506 mg, 1.29 mmol), bis(pinacolato)diboron (424.7 mg, 1.67 mmol),X-phos (92 mg, 0.193 mmol) and KOAc (379 mg, 3.86 mmol) in dry1,4-dioxane (22 mL) was placed under vacuum and back-filled with argonfor 15 min. Pd(OAc)₂ (31.7 mg, 0.142 mmol) was added to it and the flaskwas evacuated and back-filled with argon again for 5 min. This wasrefluxed for 0.5 h and then cooled to RT. Solids were filtered offthrough celite bed and the filtrate was directly used for the nextreaction. In a separate RB flask a mixture of2-bromo-6-(6-tert-butyl-1-oxo-3,4-dihydro-1H-[2,7]naphthyridin-2-yl)-benzaldehyde(0.5 g, 1.29 mmol), K₂CO₃ (888 mg, 6.44 mmol) and Cy₃P (108 mg, 0.39mmol) in dioxane-water-n-butanol (1:1:0.4) (13.6 mL) was degassed andback filled with argon for 15 min. Pd(dba)₂ (111 mg, 0.193 mmol)followed by the crude solution of the previous reaction was added to itrespectively and the whole mixture was heated at 110° C. for 1 h. Aftercompletion of the reaction, monitored by TLC and LC-MS, reaction wasfiltered and the filtrate was concentrated under reduced pressure to getcrude over normal silica gel column chromatography using MeOH-EtOAc aseluting solvent to get2-(6-tert-butyl-1-oxo-3,4-dihydro-1H-[2,7]naphthyridin-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzaldehydeas off white solid (488 mg, 61% over 2 steps). LCMS: 621.2 (M+H).

A solution of2-(6-tert-butyl-1-oxo-3,4-dihydro-1H-[2,7]naphthyridin-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-benzaldehyde(1130 mg, 1.82 mmol) in methanol-DCM (2:3) (15.2 mL) was cooled to 0° C.and a solution of NaBH₄ (344 g, 9.11 mmol) in water (3.8 mL) was addedto it drop wise. Resulting mixture was stirred for 5 min and additionalsolid sodium borohydride (344 g, 9.11 mmol) was added portion wise,stirred for 10 min After completion of the reaction, monitored by LCMS,diluted with water, extracted with DCM, dried over Na₂SO₄ andconcentrated under reduced pressure. Crude over flash silica gel usingbasic solution (DCM-MeOH—NH₄OH in 60:10:1) in DCM to get6-tert-butyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-[2,7]naphthyridin-1-onewhich was further purified by washing with diethyl ether and n-pentaneto get as off white solid6-tert-Butyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridin-3-yl}-phenyl)-3,4-dihydro-2H-[2,7]naphthyridin-1-on(215 mg, 18.96%). LCMS: 623.2 (M+H).

A solution of6-chloro-2-methyl-4-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-2H-pyridazin-3-one(280 mg, 0.801 mmol), bis(pinacolato)diboron (264.3 mg, 1.041 mmol),X-phos (57.2 mg, 0.12 mmol) and KOAc (235.7 mg, 2.402 mmol) in dry1,4-dioxane (12.5 mL) was placed under vacuum and back-filled with argonfor 15 min Pd(OAc)₂ (19.7 mg, 0.088 mmol) was added to it and the flaskwas evacuated and back-filled with argon again for 5 min. This wasrefluxed for 16 min and then cooled to RT. Solids were filtered offthrough celite bed and the filtrate was directly used for the nextreaction. In a separate RB flask a mixture of2-bromo-6-(6-tert-butyl-1-oxo-3,4-dihydro-1H-[2,7]naphthyridin-2-yl)-benzaldehyde(56) (305.0 mg, 0.788 mmol), K₂CO₃ (543.4 mg, 3.938 mmol) and Cy₃P (66.3mg, 0.236 mmol) in dioxane-water-n-butanol (1:1:0.25) (8.1 mL) wasdegassed and back filled with argon for 15 min Pd(dba)₂ (67.9 mg, 0.118mmol) followed by the crude solution of the previous reaction was addedto it respectively and the whole mixture was heated at 110° C. for 1 h.After completion of the reaction, monitored by TLC and LC-MS, reactionwas filtered and the filtrate was concentrated under reduced pressure toget crude mass which was purified over normal silica gel columnchromatography using EtOAc as eluting solvent to get2-(6-tert-butyl-1-oxo-3,4-dihydro-1H-[2,7]naphthyridin-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzaldehydeas yellow solid (291.0 mg, 59.44% over 2 steps). LCMS: 622.6 (M+H).

A solution of2-(6-tert-butyl-1-oxo-3,4-dihydro-1H-[2,7]naphthyridin-2-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzaldehyde(700 mg, 1.13 mmol) in methanol-DCM (2:3) (22.2 mL) was cooled to 0° C.and a solution of NaBH₄ (213 mg, 5.63 mmol) in water (4 mL) was added toit drop wise. Resulting mixture was stirred for 5 min and additionalsolid sodium borohydride (213 mg, 5.63 mmol) was added portion wise andagain stirred for 10 min at that temperature. After completion of thereaction, monitored by LCMS, water was added and extracted with DCM.Combined organic layer was dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. Crude was purified over flash silica gel using4-6% magic solution (DCM-MeOH—NH₄OH in 60:10:1 ratio) in DCM to get6-tert-butyl-2-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-3,4-dihydro-2H-[2,7]naphthyridin-1-one,which was further purified by washing with diethyl ether and n-pentaneto get off white solid (322 mg, 46.00%). LCMS: 624.4 (M+H).

A suspension of 6-tert-butyl-8-fluoro-2H-phthalazin-1-one (58) (1 g,4.545 mmol), 1,3-dibromo-2-methyl-benzene (2.27 g, 9.091 mmol), CuI(0.26 g, 1.364 mmol) and K₂CO₃ (0.63 g, 4.545 mmol) in DMSO (10 mL) wasdegassed followed by back-filled with argon for 15 min in a sealed tubeand the mixture was heated at 140° C. for 18 h. After completion of thereaction, monitored by LC-MS, mixture was cooled to RT and diluted withEtOAc—H₂O. Organic layer was washed with saturated brine solution, driedover anhydrous Na₂SO₄ and concentrated under reduced pressure. The crudemass was purified over normal silica gel using EtOAc-hexane as elutingsolvent to get2-(3-bromo-2-methyl-phenyl)-6-tert-butyl-8-fluoro-2H-phthalazin-1-one(4.65 g, 43%) as a light yellow solid. LCMS: 389.0 (M+), 391.2 (M+2).

A mixture of2-(3-bromo-2-methyl-phenyl)-6-tert-butyl-8-fluoro-2H-phthalazin-1-one(1.55 g, 3.985 mmol), bis(pinacolato)diboron (2.02 g, 7.969 mmol),X-phos (0.23 g, 0.398 mmol) and KOAc (0.9 g, 9.165 mmol) was taken indioxane (12 mL) in a sealed tube and degassed followed by back-filledwith argon for 15 min Pd(OAc)₂ (54 mg, 0.239 mmol) was added to it andwas heated at 80° C. for 6 h. Reaction was not completed according toLC-MS and TLC so half amount of all the reagents were added again andcontinued heating at same temperature for 16 h. After completion of thereaction, monitored by TLC & LC-MS, mixture was cooled to RT andfiltered over a bed of celite. Filtrate was concentrated under reducedpressure and crude mass was passed through a small bed of normal silicagel column chromatography using EtOAc-hexane to get semi-pure6-tert-butyl-8-fluoro-2-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2H-phthalazin-1-one(0.8 g, ˜46.01%) which was directly used for the next reaction withoutfurther purification. LCMS: 437.0 (M+H).

To a solution of6-tert-butyl-8-fluoro-2-[2-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-2H-phthalazin-1-one(2.4 g, 5.51 mmol) and6-chloro-2-methyl-4-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-2H-pyridazin-3-one(1.54 g, 4.4 mmol) in 10% aq-dioxane (69 mL), were added Cs₂CO₃ (6.75 g,20.8 mmol) and this mixture was heated at 120° C. for 3 h undermicrowave condition. After completion of the reaction, mixture wasfiltered through a bed of celite and washed with EtOAc. Filtrate wasconcentrated under reduced pressure and the crude was purified overflash silica gel column chromatography using 10% magic solution(DCM:MeOH:NH₄OH in 60:10:1 ratio) in DCM to get6-tert-butyl-8-fluoro-2-(2-methyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-2H-phthalazin-1-oneas off white solid (1.5 g, 43.7%). LC-MS: 624.2 (M+H).

To stirred solution of sodium hydroxide (3.46 g, 86.667 mmol) in water(20 mL) 3-tert-butylphenol (10 g, 66.667 mmol) was added and resultingmixture was stirred at RT for 30 min 2-(2-bromo-ethyl)-[1,3]dioxane(14.3 g, 73.33 mmol) was added to it and resulting mixture was heated toreflux for 41 h. The reaction mixture was cooled to RT and then addedEtOAc (150 mL) and with stirring acetic acid was added to pH-4, followedby dilution with water (100 mL) and EtOAc (150 mL). After partitioning,the layers were separated and the organic layer was washed with water(3×100 mL), dried over anhydrous Na₂SO₄ and concentrated under reducedpressure to get 2-[2-(3-tert-butyl-phenoxy)-ethyl]-[1,3]dioxane (16 gcrude, ˜90.79%), which was directly used for the next step withoutfurther purification. GC-MS: 264.0 (M+).

Concentrated HCl (80 mL) was cooled in an ice bath and THF (40 mL) wasadded to it. 2-[2-(3-tert-butyl-phenoxy)-ethyl]-[1,3]dioxane (10 gcrude, 37.879 mmol) in THF (40 mL) slowly at that temperature withstirring. After completion of addition, ice bath was removed andresulting mixture was stirred at RT for 3 h. After complete consumptionof starting material, ether (100 mL) was added to the mixture and layerswere separated. Combined organic layer was washed with water and driedover anhydrous Na₂SO₄ and concentrated to get crude7-tert-butyl-chroman-4-ol as light yellow oil (7.0 g crude), which wascarried to next step without further purification.

7-tert-butyl-chroman-4-ol (7 g crude, 33.981 mmol) was taken up in DCM(300 mL) and with stirring was added PCC (14.65 g, 67.961 mmol) portionwise. After completion of addition, the reaction mixture was stirred atRT for 3 h. After completion of the reaction, (monitored by LCMS),hexane was added to the reaction mixture and filtered through celitebed. Filtrate was concentrated under reduced pressure and crude mass waspurified over normal silica gel column chromatography using EtOAc-hexaneas eluting solvent to get 7-tert-butyl-chroman-4-one as light brownsolid (3.8 g, 49.18% over 2 steps). LCMS: 205.2 (M+H).

7-tert-Butyl-chroman-4-one (5.0 g, 24.51 mmol) and methane sulfonic acid(7.5 mL) were taken up in DCM (12 mL) and cooled to 0° C. Solid sodiumazide (3.2 g, 49.02 mmol) was added to this mixture and the resultingmixture was stirred at that temperature for 3 h. The reaction mixturewas poured into 20% aqueous solution of NaOH at 0° C. and stirred againfor 10 min. The whole aqueous part was extracted with CH₂Cl₂ (3×50 mL)and combined organic layer was washed with brine, dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. Crude mass was purifiedover normal silica gel column chromatography using EtOAc-hexane to get8-tert-butyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one as off whitesolid (5.0 g, 93.03%). LCMS: 220.2 (M+H).

8-tert-Butyl-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one (0.92 g, 4.201mmol), 2,6-dibromo-benzaldehyde (4.99 g, 18.904 mmol), xanthphos (109.4mg, 0.189 mmol) and Cs₂CO₃ (1.91 g, 5.881 mmol) were taken up in1,4-dioxane (15 mL) and argon gas was bubbled through the mixture for 10min Pd(dba)₂ (72.5 mg, 0.126 mmol) was added to it and stirred at 100°C. for 3 h. After completion of the reaction, monitored by TLC,resultant mixture was cooled to RT and this was partitioned betweenEtOAc and water. Organic layer collected and dried over anhydrous Na₂SO₄and concentrated under reduced pressure. Crude mass was purified overnormal silica gel column chromatography using EtOAc-hexane to get2-bromo-6-(8-tert-butyl-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-benzaldehydeas light brown solid (1.1 g, 65.09%). LCMS: 402.0 (M−H) & 404.0 (M+H).

A solution of6-chloro-2-methyl-4-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-2H-pyridazin-3-one(0.86 g, 2.464 mmol), bis(pinacolato)diboron (1001.4 mg, 3.943 mmol),X-phos (176.2 mg, 0.37 mmol) and KOAc (725.6 mg, 7.393 mmol) in dry1,4-dioxane (30 mL) was placed under vacuum and back-filled with argonfor 15 min Pd(OAc)₂ (55.3 mg, 0.246 mmol) was added to it and the flaskwas evacuated and back-filled with argon again for 5 min. This washeated at 100° C. for 30 min and then cooled to RT. Solids were filteredoff through celite bed and the filtrate was directly used for the nextreaction (M+H:316.2). In a separate RB flask a mixture of2-bromo-6-(8-tert-butyl-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-benzaldehyde(1 g, 2.481 mmol), K₂CO₃ (1.03 g, 7.444 mmol) and Cy₃P (0.21 g, 0.744mmol) in dioxane-water-n-butanol (1:1:0.4) (24 mL) was degassed and backfilled with argon for 15 min Pd(dba)₂ (0.21 g, 0.372 mmol) followed bythe crude filtrate of the previous reaction was added to it respectivelyand the whole mixture was heated at 110° C. for 1.5 h. After completionof the reaction, monitored by TLC and LC-MS, reaction was filtered andthe filtrate was concentrated under reduced pressure to get crude masswhich was purified by CombiFlash column chromatography using MeOH-EtOAcas eluting solvent to get2-(8-tert-butyl-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzaldehydeas white solid (1.0 g, 63.3% over 2 steps). LCMS: 637.6 (M+H).

A solution of2-(8-tert-butyl-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-6-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-benzaldehyde(4.6 g, 3.145 mmol) in methanol-DCM (2:3) (69 mL) was cooled to 0° C.and a solution of NaBH₄ (1.38 g, 15.723 mmol) in water (6.9 mL) wasadded to it drop wise. Resulting mixture was stirred for 10 min andadditional solid sodium borohydride (2.7 g, 31.447 mmol) was addedportion wise and again stirred for 1 h at that temperature. Aftercompletion of the reaction, (monitored by LCMS), water was added andextracted with DCM. Combined organic layer was dried over anhydrousNa₂SO₄ and concentrated under reduced pressure. Crude mass was purifiedover flash silica gel using 10-30% magic solution (DCM-MeOH—NH₄OH in60:10:1 ratio) in DCM to get8-tert-butyl-4-(2-hydroxymethyl-3-{1-methyl-5-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-6-oxo-1,6-dihydro-pyridazin-3-yl}-phenyl)-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one,which was further purified by washing with diethyl ether and n-pentaneto get off white solid (2.12 g, 45.87%). LCMS: 639.2 (M+H).

A solution of6-chloro-4-(5-methanesulfonyl-pyridin-2-ylamino)-2-methyl-2H-pyridazin-3-one(0.78 g, 2.484 mmol), bis(pinacolato)diboron (1009.5 mg, 3.975 mmol),X-phos (177.6 mg, 0.373 mmol) and KOAc (731.4 mg, 7.452 mmol) in dry1,4-dioxane (70 mL) was placed under vacuum and back-filled with argonfor 15 min. Pd(OAc)₂ (55.8 mg, 0.248 mmol) was added to it and the flaskwas evacuated and back-filled with argon again for 5 min. This washeated at 100° C. for 1 h and then cooled to RT. This solution wasdirectly used for the next reaction (M+H:323.6). In a separate RB flaska mixture of2-bromo-6-(8-tert-butyl-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-benzaldehyde(1 g, 2.481 mmol), K₂CO₃ (1.71 g, 12.407 mmol) and Cy₃P (0.21 g, 0.744mmol) in dioxane-water-n-butanol (1:1:0.25) (27 mL) was degassed andback filled with argon for 15 min Pd(dba)₂ (0.21 g, 0.372 mmol) followedby the crude solution of the previous reaction was added to itrespectively and the whole mixture was heated at 110° C. for 1.5 h.After completion of the reaction, monitored by TLC and LC-MS, reactionwas filtered and the filtrate was concentrated under reduced pressure toget crude mass which was purified by CombiFlash column chromatographyusing MeOH-EtOAc as eluting solvent to get2-(8-tert-butyl-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-6-[5-(5-methanesulfonyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzaldehydeas light yellow solid (510 mg, 34.16% over 2 steps). LCMS: 602.2 (M+H).

A solution of2-(8-tert-butyl-5-oxo-2,3-dihydro-5H-benzo[f][1,4]oxazepin-4-yl)-6-[5-(5-methanesulfonyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-benzaldehyde(1 g, 1.572 mmol) in methanol-DCM (2:3) (30 mL) was cooled to 0° C. anda solution of NaBH₄ (0.3 g, 7.862 mmol) in water (3 mL) was added to itdrop wise. Resulting mixture was stirred for 10 min and additional solidsodium borohydride (0.59 g, 15.723 mmol) was added portion wise andagain stirred for 1 h at that temperature. After completion of thereaction, monitored by LCMS, water was added and extracted with DCM.Combined organic layer was dried over anhydrous Na₂SO₄ and concentratedunder reduced pressure. Crude mass was purified over flash silica gelusing 10-30% magic solution (DCM-MeOH—NH4OH in 60:10:1 ratio) in DCM toget8-tert-butyl-4-[2-hydroxymethyl-3-[5-(5-methanesulfonyl-pyridin-2-ylamino)-1-methyl-6-oxo-1,6-dihydro-pyridazin-3-yl]-phenyl]-3,4-dihydro-2H-benzo[f][1,4]oxazepin-5-one,which was further purified by washing with diethyl ether and n-pentaneto get off white solid (540 mg, 56.89%). LCMS: 604.4 (M+H).

Biological Examples

Bruton's Tyrosine Kinase (BTK) Inhibition Assay

The assay is a capture of radioactive ³³P phosphorylated product throughfiltration. The interactions of BTK, biotinylated SH₂ peptide substrate(Src homology), and ATP lead to phosphorylation of the peptidesubstrate. Biotinylated product is bound streptavidin sepharose beads.All bound, radiolabeled products are detected by scintillation counter.

Plates assayed are 96-well polypropylene (Greiner) and 96-well 1.2 μmhydrophilic PVDF filter plates (Millipore). Concentrations reported hereare final assay concentrations: 10-100 μM compounds in DMSO (Burdick andJackson), 5-10 nM BTK enzyme (His-tagged, full-length), 30 μM peptidesubstrate (Biotin-Aca-AAAEEIYGEI-NH₂), 100 μM ATP (Sigma), 8 mMimidazole (Sigma, pH 7.2), 8 mM glycerol-2-phosphate (Sigma), 200 μMEGTA (Roche Diagnostics), 1 mM MnCl₂ (Sigma), 20 mM MgCl₂ (Sigma), 0.1mg/ml BSA (Sigma), 2 mM DTT (Sigma), 1 μCi ³³P ATP (Amersham), 20%streptavidin sepharose beads (Amersham), 50 mM EDTA (Gibco), 2 M NaCl(Gibco), 2 M NaCl w/1% phosphoric acid (Gibco), microscint-20 (PerkinElmer).

IC₅₀ determinations are calculated from 10 data points per compoundutilizing data produced from a standard 96-well plate assay template.One control compound and seven unknown inhibitors were tested on eachplate and each plate was run twice. Typically, compounds were diluted inhalf-log starting at 100 μM and ending at 3 nM. The control compound wasstaurosporine. Background was counted in the absence of peptidesubstrate. Total activity was determined in the presence of peptidesubstrate. The following protocol was used to determine BTK inhibition.

1) Sample preparation: The test compounds were diluted at half-logincrements in assay buffer (imidazole, glycerol-2-phosphate, EGTA,MnCl₂, MgCl₂, BSA).

2) Bead preparation

-   -   a.) rinse beads by centrifuging at 500 g    -   b.) reconstitute the beads with PBS and EDTA to produce a 20%        bead slurry

3) Pre-incubate reaction mix without substrate (assay buffer, DTT, ATP,³³P ATP) and mix with substrate (assay buffer, DTT, ATP, ³³P ATP,peptide substrate) 30° C. for 15 min

4) To start assay, pre-incubate 10 μL BTK in enzyme buffer (imidazole,glycerol-2-phosphate, BSA) and 10 μL of test compounds for 10 min at RT.

5) Add 30 μL reaction mixture without or with substrate to BTK andcompounds.

6) Incubate 50 μL total assay mix for 30 min at 30° C.

7) Transfer 40 μL of assay to 150 μL bead slurry in filter plate to stopreaction.

8) Wash filter plate after 30 min, with following steps

-   -   a. 3×250 μL NaCl    -   b. 3×250 μL NaCl containing 1% phosphoric acid    -   c. 1×250 μL H₂O

9) Dry plate for 1 h at 65° C. or overnight at RT

10) Add 50 μL microscint-20 and count ³³P cpm on scintillation counter.

-   -   Calculate percent activity from raw data in cpm        percent activity=(sample−bkg)/(total activity−bkg)×100    -   Calculate IC₅₀ from percent activity, using one-site dose        response sigmoidal model        y=A+((B−A)/(1+((x/C)^(D)))))    -   x=cmpd conc, y=% activity, A=min, B=max, C=IC₅₀, D=1 (hill        slope)        Bruton's Tyrosine Kinase (BTK) Inhibition TR-FRET (Time Resolved        FRET) Assay

This BTK competition assay measures compound potency (IC50) for theinactivated state of Bruton's Tyrosine Kinase using FRET(Förster/Flouresence Resonance Energy Transfer) technology. The BTK-Eucomplex was incubated on ice one hour prior to use at a startingconcentration of 50 nM BTK-Bioease™: 10 nM Eu-streptavidin (Perkin-ElmerCatalog# AD0062). The assay buffer consisted of 20 mM HEPES (pH 7.15),0.1 mM DTT, 10 mM MgCl₂, 0.5 mg/ml BSA with 3% Kinase Stabilizer(Fremont Biosolutions, Catalog # STB-K02). After 1 h, the reactionmixture from above was diluted 10 fold in assay buffer to make 5 nM BTK:1 nM Eu-Streptavidin complex (donor fluorophore). 18 μl of a mixture of0.11 nM BTK-Eu and 0.11 nM Kinase Tracer 178 (Invitrogen, Catalog #PV5593) with BTK-Eu alone as no negative control, was then dispensedinto 384-well flat bottom plates (Greiner, 784076). Compounds to betested in assay were prepared as 10× concentrations and serial dilutionin half-log increments was performed in DMSO so as to generate 10 pointcurves. To initiate the FRET reaction, compounds prepared as 10× stockin DMSO was added to the plates and the plates were incubated 18-24 h at14° C.

After the incubation the plates were read on a BMG Pherastar Fluorescentplate reader (or equivalent) and used to measure the emission energyfrom the europium donor fluorophore (620 nm emission) and the FRET (665nm emission). The negative control well values were averaged to obtainthe mean minimum. The positive “no inhibitor” control wells wereaveraged to obtain the mean maximum. Percent of maximal FRET wascalculated using following equation:% maxFRET=100×[(FSR_(cmpd)−FSR_(mean min))/(FSR_(mean max)−FSR_(mean min))]where FSR=FRET Signal ratio. % Max FRET curves were plotted in ActivityBase (Excel) and the IC50(%), hill slope, z′ and % CV were determined.The mean IC50 and standard deviation will be derived from duplicatecurves (singlet inhibition curves from two independent dilutions) usingMicrosoft Excel.

Representative compound data for this assay are listed below in TableII.

TABLE II Compound FRET IC50 (μmol) 1 0.01118 2 0.00112 3 0.0526 40.03195 5 0.0137 6 0.01462 7 0.0065 8 0.00177 9 0.00424Inhibition of B Cell Activation in Whole Blood Measured by CD69Expression

A procedure to test the ability of BTK inhibitors to suppress B cellreceptor-mediated activation of B cells in human blood is as follows:

Human whole blood (HWB) is obtained from healthy volunteers, with thefollowing restrictions: 24 hr drug-free, non-smokers. Blood is collectedby venipuncture into Vacutainer tubes anticoagulated with sodiumheparin. Test compounds are diluted to ten times the desired startingdrug concentration in PBS (20×), followed by three-fold serial dilutionsin 10% DMSO in PBS to produce a nine point dose-response curve. 5.5 μlof each compound dilution is added in duplicate to a 2 ml 96-well Vbottom plate (Analytical Sales and Services, #59623-23); 5.5 μl of 10%DMSO in PBS is added to control and no-stimulus wells. HWB (100 μl) isadded to each well, and after mixing the plates are incubated at 37C, 5%CO₂, 100% humidity for 30 minutes. Goat F(ab′)2 anti-human IgM (SouthernBiotech, #2022-14) (10 μl of a 500 μg/ml solution, 50 μg/ml finalconcentration) is added to each well (except the no-stimulus wells) withmixing and the plates are incubated for an additional 20 hours.

At the end of the 20 hour incubation, samples are incubated withflorescent-probe-labeled antibodies (15 μl PE Mouse anti-Human CD20, BDPharmingen, #555623, and/or 20 μl APC Mouse anti-Human CD69, BDPharmingen #555533) for 30 minutes, at 37C, 5% CO₂, 100% humidity.Included are induced control, unstained and single stains forcompensation adjustments and initial voltage settings. Samples are thenlysed with 1 ml of 1× Pharmingen Lyse Buffer (BD Pharmingen #555899),and plates are centrifuged at 1800 rpm for 5 minutes. Supernatants areremoved via suction and the remaining pellets are lysed again withanother 1 ml of 1× Pharmingen Lyse Buffer, and plates are spun down asbefore. Supernatants are aspirated and remaining pellets are washed inFACs buffer (PBS+1% FBS). After a final spin, the supernantants areremoved and pellets are resuspended in 180 μl of FACs buffer. Samplesare transferred to a 96 well plate suitable to be run on the HTS 96 wellsystem on the BD LSR II flow cytometer.

Using appropriate excitation and emission wavelengths for thefluorophores used, data are acquired and percent positive cell valuesare obtained using Cell Quest Software. Results are initially analyzedby FACS analysis software (Flow Jo). The IC50 for test compounds isdefined as the concentration which decreases by 50% the percentage ofCD69-positive cells that are also CD20-positive after stimulation byanti-IgM (average of 8 control wells, after subtraction of the averageof 8 wells for the no-stimulus background). The IC50 values arecalculated using XLfit software version 3, equation 201.

Inhibition of B-Cell Activation-B Cell FLIPR Assay in Ramos Cells

Inhibition of B-cell activation by compounds of the present invention isdemonstrated by determining the effect of the test compounds on anti-IgMstimulated B cell responses.

The B cell FLIPR assay is a cell based functional method of determiningthe effect of potential inhibitors of the intracellular calcium increasefrom stimulation by an anti-IgM antibody. Ramos cells (human Burkitt'slymphoma cell line. ATCC-No. CRL-1596) were cultivated in Growth Media(described below). One day prior to assay, Ramos cells were resuspendedin fresh growth media (same as above) and set at a concentration of0.5×10⁶/mL in tissue culture flasks. On day of assay, cells are countedand set at a concentration of 1×10⁶/mL1 in growth media supplementedwith 1 μM FLUO-3AM (TefLabs Cat-No. 0116, prepared in anhydrous DMSO and10% Pluronic acid) in a tissue culture flask, and incubated at 37° C.(4% CO₂) for one h. To remove extracellular dye, cells were collected bycentrifugation (5 min, 1000 rpm), resuspended in FLIPR buffer (describedbelow) at 1×10⁶ cells/mL and then dispensed into 96-well poly-D-lysinecoated black/clear plates (BD Cat-No. 356692) at 1×10⁵ cells per well.Test compounds were added at various concentrations ranging from 100 μMto 0.03 μM (7 concentrations, details below), and allowed to incubatewith cells for 30 min at RT. Ramos cell Ca²⁺ signaling was stimulated bythe addition of 10 μg/mL anti-IgM (Southern Biotech, Cat-No. 2020-01)and measured on a FLIPR (Molecular Devices, captures images of 96 wellplates using a CCD camera with an argon laser at 480 nM excitation).

Media/Buffers:

Growth Medium: RPMI 1640 medium with L-glutamine (Invitrogen, Cat-No.61870-010), 10% Fetal Bovine Serum (FBS, Summit Biotechnology Cat-No.FP-100-05); 1 mM Sodium Pyruvate (Invitrogen Cat. No. 11360-070).

FLIPR buffer: HBSS (Invitrogen, Cat-No. 141175-079), 2 mM CaCl₂ (SigmaCat-No. C-4901), HEPES (Invitrogen, Cat-No. 15630-080), 2.5 mMProbenecid (Sigma, Cat-No. P-8761), 0.1% BSA (Sigma, Cat-No.A-7906), 11mM Glucose (Sigma, Cat-No.G-7528)

Compound Dilution Details:

In order to achieve the highest final assay concentration of 100 μM, 24μL of 10 mM compound stock solution (made in DMSO) is added directly to576 μL of FLIPR buffer. The test compounds are diluted in FLIPR Buffer(using Biomek 2000 robotic pipettor) resulting in the following dilutionscheme: vehicle, 1.00×10⁻⁴ M, 1.00×10⁻⁵, 3.16×10⁻⁶, 1.00×10⁻⁶,3.16×10⁻⁷, 1.00×10⁻⁷, 3.16×10⁻⁸.

Assay and Analysis:

Intracellular increases in calcium were reported using a max-minstatistic (subtracting the resting baseline from the peak caused byaddition of the stimulatory antibody using a Molecular Devices FLIPRcontrol and statistic exporting software. The IC₅₀ was determined usinga non-linear curve fit (GraphPad Prism software).

Mouse Collagen-Induced Arthritis (mCIA)

On day 0 mice are injected at the base of the tail or several spots onthe back with an emulsion of Type II Collagen (i.d.) in CompleteFreund's adjuvant (CFA). Following collagen immunization, animals willdevelop arthritis at around 21 to 35 days. The onset of arthritis issynchronized (boosted) by systemic administration of collagen inIncomplete Freund's adjuvant (IFA; i.d.) at day 21 Animals are examineddaily after day 20 for any onset of mild arthritis (score of 1 or 2; seescore description below) which is the signal to boost. Following boost,mice are scored and dosed with candidate therapeutic agents for theprescribed time (typically 2-3 weeks) and dosing frequency, daily (QD)or twice-daily (BID).

Rat Collagen-Induced Arthritis (rCIA)

On day 0, rats are injected with an emulsion of Bovine Type II Collagenin Incomplete Freund's adjuvant (IFA) is injected intradermally (i.d.)on several locations on the back. A booster injection of collagenemulsion is given around day 7, (i.d.) at the base of the tail oralternative sites on the back. Arthritis is generally observed 12-14days after the initial collagen injection. Animals may be evaluated forthe development of arthritis as described below (Evaluation ofarthritis) from day 14 onwards. Animals are dosed with candidatetherapeutic agents in a preventive fashion starting at the time ofsecondary challenge and for the prescribed time (typically 2-3 weeks)and dosing frequency, daily (QD) or twice-daily (BID).

Evaluation of Arthritis:

In both models, developing inflammation of the paws and limb joints isquantified using a scoring system that involves the assessment of the 4paws following the criteria described below:

Scoring: 1=swelling and/or redness of paw or one digit.

-   -   2=swelling in two or more joints.    -   3=gross swelling of the paw with more than two joints involved.    -   4=severe arthritis of the entire paw and digits.

Evaluations are made on day 0 for baseline measurement and startingagain at the first signs or swelling for up to three times per weekuntil the end of the experiment. The arthritic index for each mouse isobtained by adding the four scores of the individual paws, giving amaximum score of 16 per animal.

Rat In Vivo Asthma Model

Male Brown-Norway rats are sensitized i.p. with 100 μg of OA (ovalbumin)in 0.2 ml alum once every week for three weeks (day 0, 7, and 14). Onday 21 (one week following last sensitization), the rats are dosed q.d.with either vehicle or compound formulation subcutaneously 0.5 hourbefore OA aerosol challenge (1% OA for 45 minutes) and terminated 4 or24 hours after challenge. At time of sacrifice, serum and plasma arecollected from all animals for serology and PK, respectively. A trachealcannula is inserted and the lungs are lavaged 3× with PBS. The BAL fluidis analyzed for total leukocyte number and differential leukocytecounts. Total leukocyte number in an aliquot of the cells (20-100 μl) isdetermined by Coulter Counter. For differential leukocyte counts, 50-200μl of the sample is centrifuged in a Cytospin and the slide stained withDiff-Quik. The proportions of monocytes, eosinophils, neutrophils andlymphocytes are counted under light microscopy using standardmorphological criteria and expressed as a percentage. Representativeinhibitors of BTK show decreased total leucocyte count in the BAL of OAsensitized and challenged rats as compared to control levels.

The foregoing invention has been described in some detail by way ofillustration and example, for purposes of clarity and understanding. Itwill be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

All patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

The invention claimed is:
 1. A compound of Formula I,

wherein: n is 1 or 2; R¹ is —C(═O)R^(1′), —S(═O)₂R^(1′), or—OC(R^(1′))₂CH₂OH; R^(1′) is methyl or morpholine; R² is H or F; R³ ischloro or C(CH₂)₂R^(3′); R^(3′) is methyl, cyano, or hydroxymethyl; X isCH, CH₂, or N; X² is N; X³ is CH or N; and Y is CH or O; with theproviso that when n is 2, both X are CH₂; or a pharmaceuticallyacceptable salt thereof.
 2. The compound of claim 1, wherein R² is H. 3.The compound of claim 1, wherein R³ is tert-butyl.
 4. The compound ofclaim 1, wherein X³ is CH.
 5. The compound of claim 1, wherein X² is N.6. The compound of claim 1, wherein R¹ is —C(═O)R^(1′) and R^(1′) ismorpholine.
 7. The compound of claim 1, wherein n is
 1. 8. The compoundof claim 1, wherein X is CH or CH₂.
 9. The compound of claim 1, whereinY is CH or CH₂.
 10. The compound of claim 5, wherein n is 2 and Y is O.11. The compound of claim 10, wherein R¹ is —S(═O)₂R^(1′) and R^(1′) ismethyl or R¹ is —C(═O)R^(1′) and R^(1′) is morpholine.
 12. The compoundof claim 1, selected from the group consisting of:2-[2-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)pyridin-2-yl]amino]-6-oxopyridazin-3-yl]phenyl]-1-oxo-3,4-dihydroisoquinolin-6-yl]-2-methylpropanenitrile;2-[8-fluoro-2-[2-(hydroxymethyl)-3-[5-[[5-(1-hydroxy-2-methylpropan-2-yl)oxypyridin-2-yl]amino]-1-methyl-6-oxopyridazin-3-yl]phenyl]-1-oxoisoquinolin-6-yl]-2-methylpropanenitrile;4-[2-(hydroxymethyl)-3-[1-methyl-5-[(5-methylsulfonylpyridin-2-yl)amino]-6-oxopyridazin-3-yl]phenyl]-8-(1-hydroxy-2-methylpropan-2-yl)-2,3-dihydro-1,4-benzoxazepin-5-one;6-tert-butyl-2-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)pyridin-2-yl]amino]-6-oxopyridazin-3-yl]phenyl]-3,4-dihydro-2,7-naphthyridin-1-one;6-tert-butyl-8-fluoro-2-[2-methyl-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)pyridin-2-yl]amino]-6-oxopyridazin-3-yl]phenyl]phthalazin-1-one;8-tert-butyl-4-[2-(hydroxymethyl)-3-[1-methyl-5-[[5-(morpholine-4-carbonyl)pyridin-2-yl]amino]-6-oxopyridazin-3-yl]phenyl]-2,3-dihydro-1,4-benzoxazepin-5-one;and8-tert-butyl-4-[2-(hydroxymethyl)-3-[1-methyl-5-[(5-methylsulfonylpyridin-2-yl)amino]-6-oxopyridazin-3-yl]phenyl]-2,3-dihydro-1,4-benzoxazepin-5-one.13. A pharmaceutical composition, comprising a therapeutically effectiveamount of a compound of claim 1, or a pharmaceutically acceptable saltthereof, admixed with at least one pharmaceutically acceptable carrier,excipient or diluent.